Large-scale Population Studies Research Articles

The unique association between the level of plateletcrit and the prevalence of diabetic kidney disease: a cross-sectional study.

The activation of platelets in individuals with type 2 diabetes mellitus (T2DM) triggers inflammation and hemodynamic abnormalities, contributing to the development of diabetic kidney disease (DKD). Despite this, research into the relationship between plateletcrit (PCT) levels and DKD is sparse, with inconsistent conclusions drawn regarding the connection between various platelet parameters and DKD. This highlights the necessity for comprehensive, large-scale population studies. Therefore, our objective is to explore the association between PCT levels and various platelet parameters in relation to DKD. In this cross-sectional study, hematological parameter data were collected from a cohort of 4,302 hospitalized Chinese patients. We analyzed the relationships between PCT, platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), platelet large cell ratio (P-LCR), and DKD, along with the urinary albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the diagnostic potential of these parameters. DKD patients exhibited significantly higher PCT levels compared to those without DKD. Multivariate regression analysis identified elevated PCT and PLT levels as potential independent risk factors for both DKD and UACR, while lower MPV levels might serve as independent protective factors for eGFR. The areas under the ROC curve for PCT in relation to DKD and UACR (≥30 mg/g) were 0.523 and 0.526, respectively. The area under the ROC curve for PLT in relation to UACR (≥30 mg/g) was 0.523. PCT demonstrates a weak diagnostic value for T2DM patients at risk of developing DKD and experiencing proteinuria, and PLT shows a similarly modest diagnostic utility for detecting proteinuria. These insights contribute to a deeper understanding of the complex dynamics involved in DKD. Additionally, incorporating these markers into routine clinical assessments could enhance risk stratification, facilitating early interventions and personalized management strategies.

Malaria resistance-related biological adaptation and complex evolutionary footprints inferred from one integrative Tai-Kadai-related genomic resource

Pathogen‒host adaptative interactions and complex population demographical processes, including admixture, drift, and Darwen selection, have considerably shaped the Neolithic-to-Modern Western Eurasian population structure and genetic susceptibility to modern human diseases. However, the genetic footprints of evolutionary events in East Asia remain unknown due to the underrepresentation of genomic diversity and the design of large-scale population studies. We reported one aggregated database of genome-wide SNP variations from 796 Tai-Kadai (TK) genomes, including that of Bouyei first reported here, to explore the genetic history, population structure, and biological adaptative features of TK people from southern China and Southeast Asia. We found geography-related population substructure among TK people using the state-of-the-art population genetic structure reconstruction techniques based on the allele frequency spectrum and haplotype-resolved phased fragments. We found that the northern TK people from Guizhou harbored one TK-dominant ancestry maximized in the Bouyei people, and the southern TK people from Thailand were more influenced by Southeast Asians and indigenous people. We reconstructed fitted admixture models and demographic graphs, which showed that TK people received gene flow from ancient southern rice farmer-related lineages related to the Hmong-Mien and Austroasiatic people and from northern millet farmers associated with the Sino-Tibetan people. Biological adaptation focused on our identified unique TK lineages related to Bouyei, which showed many adaptive signatures conferring Malaria resistance and low-rate lipid metabolism. Further gene enrichment, the allele frequency distribution of derived alleles, and their correlation with the incidence of Malaria further confirmed that CR1 played an essential role in the resistance of Malaria in the ancient "Baiyue" tribes.

Gene polymorphism as a cause of hemorrhagic complications in patients with non-valvular atrial fibrillation treated with oral vitamin K-independent anticoagulants.

Atrial fibrillation (AF) accounts for 40% of all cardiac arrhythmias and is associated with a high risk of stroke and systemic thromboembolic complications. Dabigatran, rivaroxaban, apixaban, and edoxaban are direct oral anticoagulants (DOACs) that have been proven to prevent stroke in patients with non-valvular AF. This review summarizes the pharmacokinetics, pharmacodynamics, and drug interactions of DOACs, as well as new data from pharmacogenetic studies of these drugs. This review is aimed at analyzing the scientific literature on the gene polymorphisms involved in the metabolism of DOACs. We searched PubMed, Cochrane, Google Scholar, and CyberLeninka (Russian version) databases with keywords: 'dabigatran', 'apixaban', 'rivaroxaban', 'edoxaban', 'gene polymorphism', 'pharmacogenetics', 'ABCB1', 'CES1', 'SULT1A', 'ABCG2', and 'CYP3A4'. The articles referred for this review include (1) full-text articles; (2) study design with meta-analysis, an observational study in patients taking DOAC; and (3) data on the single-nucleotide polymorphisms and kinetic parameters of DOACs (plasma concentration), or a particular clinical outcome, published in English and Russian languages during the last 10 years. The ages of the patients ranged from 18 to 75 years. Out of 114 reviewed works, 24 were found eligible. As per the available pharmacogenomic data, polymorphisms affecting DOACs are different. This may aid in developing individual approaches to optimize DOAC pharmacotherapy to reduce the risk of hemorrhagic complications. However, large-scale population studies are required to determine the dosage of the new oral anticoagulants based on genotyping. Information on the genetic effects is limited owing to the lack of large-scale studies. Uncovering the mechanisms of the genetic basis of sensitivity to DOACs helps in developing personalized therapy based on patient-specific genetic variants and improves the efficacy and safety of DOACs in the general population.

A history of cardiovascular magnetic resonance imaging in clinical practice and population science.

Cardiovascular magnetic resonance (CMR) imaging has become an invaluable clinical and research tool. Starting from the discovery of nuclear magnetic resonance, this article provides a brief overview of the key developments that have led to CMR as it is today, and how it became the modality of choice for large-scale population studies.

Pupil involving oculomotor palsy- Examination, Cause and Outcome Outcome

BACKGROUND: A patient with a third cranial nerve (CN III) palsy can be a stress inducing event for an optometrist due to the potentially life-threatening etiologies and infrequency of their presentation. The pathogenesis of a CN III palsy can vary from innocuous to life threatening. Palsy of the third cranial nerve results in an impairment of eye movement and / or pupillary response to light depending on the extent of the palsy. CASE REPORT: This case reviews a recent onset of a complete right oculomotor palsy. Literature of similar cases detail the likelihood of variable causes, and while a diagnostic work-up is indicated based on the risk, the etiology of the palsy in this case was determined to be more benign in nature. CONCLUSION: Large scale population studies in the literature reveal the etiology of a CN III palsy from life-threatening conditions is lower than indicated based on published case reports. However, a complete evaluation of a patient including neuro-imagining is still warranted due to the potential life-threatening complications. Further population studies with increased diversity need to be performed to advance knowledge in this area.

Noninvasive Assessment of Diabetic Kidney Disease With MRI: Hype or Hope?

Owing to the increasing prevalence of diabetic mellitus, diabetic kidney disease (DKD) is presently the leading cause of chronic kidney disease and end-stage renal disease worldwide. Early identification and disease interception is of paramount clinical importance for DKD management. However, current diagnostic, disease monitoring and prognostic tools are not satisfactory, due to their low sensitivity, low specificity, or invasiveness. Magnetic resonance imaging (MRI) is noninvasive and offers a host of contrast mechanisms that are sensitive to pathophysiological changes and risk factors associated with DKD. MRI tissue characterization involves structural and functional information including renal morphology (kidney volume (TKV) and parenchyma thickness using T1- or T2-weighted MRI), renal microstructure (diffusion weighted imaging, DWI), renal tissue oxygenation (blood oxygenation level dependent MRI, BOLD), renal hemodynamics (arterial spin labeling and phase contrast MRI), fibrosis (DWI) and abdominal or perirenal fat fraction (Dixon MRI). Recent (pre)clinical studies demonstrated the feasibility and potential value of DKD evaluation with MRI. Recognizing this opportunity, this review outlines key concepts and current trends in renal MRI technology for furthering our understanding of the mechanisms underlying DKD and for supplementing clinical decision-making in DKD. Progress in preclinical MRI of DKD is surveyed, and challenges for clinical translation of renal MRI are discussed. Future directions of DKD assessment and renal tissue characterization with (multi)parametric MRI are explored. Opportunities for discovery and clinical break-through are discussed including biological validation of the MRI findings, large-scale population studies, standardization of DKD protocols, the synergistic connection with data science to advance comprehensive texture analysis, and the development of smart and automatic data analysis and data visualization tools to further the concepts of virtual biopsy and personalized DKD precision medicine. We hope that this review will convey this vision and inspire the reader to become pioneers in noninvasive assessment and management of DKD with MRI. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Genetic Control of Alternative Splicing and its Distinct Role in Colorectal Cancer Mechanisms

Dysregulation of alternative splicing is implicated in many human diseases and understanding the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of cancers. We aimed to provide a comprehensive functional dissection of splicing quantitative trait loci (sQTLs) in cancer and focus on elucidating its distinct role in colorectal cancer (CRC) mechanisms. Firstly, we performed a comprehensive sQTL analysis to identify genetic variants that control mRNA splicing across 33 cancer types from TCGA and independently validated in our 154 CRC tissues. Then, large-scale, multicenter, multiethnic case-control studies (34,585 cases and 76,023 controls) were conducted to examine the association of these sQTLs with CRC risk. A series of biological experiments in vitro and in vivo were performed to investigate the potential mechanisms of the candidate sQTLs and target genes. The molecular characterization of sQTL revealed its distinct role in cancer susceptibility. Tumor-specific sQTL further showed better response to cancer development. Besides, functionally informed polygenetic risk score highlighted the potentiality of sQTLs in the CRC prediction. Complemented by large-scale population studies, we identified that the risk allele (T) of a multi-ancestry-associated sQTL rs61746794 significantly increased the risk of CRC in Chinese populations (OR=1.20, 95% CI=1.12-1.29, P=8.82×10-7) and European populations (OR=1.11, 95% CI=1.07-1.16, P=1.13×10-7). rs61746794-T facilitated PRMT7 exon 16 splicing mediated by the RBP PRPF8, thus increasing the level of canonical PRMT7 isoform (PRMT7-V2). Overexpression of PRMT7-V2 significantly enhanced the growth of CRC cells and xenograft tumors, compared with PRMT7-V1. Mechanistically, PRMT7-V2 functions as an epigenetic writer that catalyzes the arginine methylation of H4R3 and H3R2, subsequently regulating diverse biological processes, including YAP, AKT, and KRAS pathway. A selective PRMT7 inhibitor, SGC3027, exhibited antitumor effects on human CRC cells. Our study provide an informative sQTLs resource and insights into the regulatory mechanisms linking splicing variants to cancer risk, serving as biomarkers and therapeutic targets.

Association of medicinal plant consumption with all-cause mortality and cognitive impairment in older adult: A large prospective cohort study

BackgroundPanax ginseng and other medicinal plants have long been believed to have beneficial effects on health, and there is substantial evidence supporting their mechanisms of action. However, the extent of the health benefits derived from consuming these medicinal plants lacks substantial evidence from large-scale longitudinal population studies. The purpose of this study was to analyze the effect of consuming these medicinal plants on all-cause mortality and cognitive impairment. MethodsA population-based cohort study was conducted using the Chinese Longitudinal Healthy Longevity Survey (CLHLS), which was established in 1998 and has been followed up till now. The main exposure was the frequency of eating medicinal plants, including Panax ginseng, Astragalus membranaceus, Lycium barbarum, Angelica sinensis, etc. According to the consumption patterns of medicinal plants, the participants were divided into three groups: frequent use, occasional use, and rarely or never use group. The participants were individually tracked to determine their mortality and cognitive impairment status during the period from 2008 to 2018. Cox proportional hazards regression and competing risk model were used to calculate the hazard ratio (HR) for the association between the use of medicinal plants and the all-cause mortality and cognitive impairment. ResultsAmong 13,918 participants, the average age was 87.2 ± 11.3 years old, and 70.1% (9,754/13,918) of the participants died during follow-up. The proportion of those frequently using, occasionally using, and rarely using medicinal plants was 8.4%, 20.7%, and 70.8%, respectively. Compared with the rarely or never use group, the occasional and frequent use groups demonstrated significantly lower risks for all-cause mortality, with HR of 0.75 (95% CI: 0.71 – 0.79) and 0.53 (95% CI: 0.49 – 0.58), respectively. The protective effect of medicinal plants against all-cause mortality decreased with increasing age in the subgroup analysis. Additionally, frequent use of medicinal plants reduced the risk of cognitive impairment in the competing risk model (HR = 0.73, 95% CI: 0.60 – 0.87). However, there was no protective effect on cognitive function for those who occasional use medicinal plants. ConclusionIn elderly individuals, occasional and frequent use of medicinal plants was associated with reductions in risk of all-cause mortality, and frequent use of medicinal plants could reduce the risk of cognitive impairment.

Characterization of global research trends and prospects on sudden coronary death: A literature visualization analysis

BackgroundSudden coronary death is a major global public health issue that has a significant impact on both individuals and society. Nowadays, scholars are active in sudden coronary death all over the world. However, no relevant bibliometric studies have been published. Here, we aim to gain a better understanding the current state of research and to explore potential new research directions through bibliometric analysis. MethodsArticles and reviews on sudden coronary death from 2012 to 2023 were retrieved from the Web of Science Core Collection (WoSCC). The topic search was conducted using the following keywords: (((“sudden cardiac death” OR “sudden death”) AND (coronary OR “myocardial infarction”)) OR “sudden coronary death”). Knowledge maps of authors, countries, institutions, journals, keywords, and citations were conducted by CiteSpace. Publication dynamics, hotspots, and frontiers were analyzed independently by authors. ResultsA total of 2914 articles were identified from January 1, 2012 to June 20, 2023. The USA (n = 972) contributed the greatest absolute productivity and UK (centrality = 0.13) built a robust global collaboration. Harvard University was the institution with the highest number of publications (n = 143). Huikuri HV and Junttila MJ were the most published authors who devoted to searching for biomarkers of sudden coronary death. American Journal of Cardiology was the journal with the most publications, and Circulation was the most cited journal. Left ventricular ejection fraction, society, inflammation, and fractional flow reserve became novel burst words that lasted until 2023. Research on etiology and pathology, role of early risk factors in risk stratification, potential predictive biomarkers and novel measurement methods for the prevention and management of sudden coronary death were identified as the research hotspots and frontiers. ConclusionOur knowledge and understanding of sudden coronary death have significantly improved. Ongoing efforts should focus on the various etiologies and pathologies of sudden coronary death. Furthermore, a novel sudden coronary death risk model, large-scale population studies, and the rational use of multiple indicators to individualize the assessment of sudden coronary death and other risk factors are other emerging research trends.

An Epidemiologic Study of the Incidence and Mortality of Abdominal Aortic Aneurysms in Koreans Aged ≥50 Years from 2009 to 2018 Based on a National Database.

Large-scale population studies of the incidence of and mortality from abdominal aortic aneurysm (AAA) are needed to develop healthcare policies and priorities. The aim of this study was to estimate the incidence of AAA and the all-cause mortality from it among Koreans aged ≥50 years from 2009 to 2018 using data from the Korean National Health Insurance System Database. The crude and standardized incidence and all-cause mortality of the disease among patients with unruptured AAA were calculated. A total of 73,933 AAA patients were identified. The overall incidence of AAA in adults ≥50 years during the study period was 37.5 per 100,000 population (49.7 per 100,000 in men and 26.8 per 100,000 in women), with an increase from 32.33 per 100,000 persons in 2009 to 46.85 per 100,000 in 2018. The crude all-cause mortality rate of patients with untreated AAA was 21.26/100 person-years in 2009 and 8.87/100 person-years in 2018, with decreasing trends observed both in men and women. This nationwide study showed that the incidence of AAA in Koreans aged ≥50 years in 2018 was 63.40 per 100,000 in men and 32.07 per 100,000 in women. The overall rates were 0.06% and 0.03%, respectively, with an increasing trend. Mortality has decreased in both treated and untreated patients. The observed increase in incidence suggests a rising burden of AAA in the Korean population, particularly among men. The decreasing mortality rates may indicate improvements in the management and treatment of AAA over the study period.

Genetic control of N-glycosylation of human blood plasma proteins.

Glycosylation is an important protein modification, which influences the physical and chemical properties as well as biological function of these proteins. Large-scale population studies have shown that the levels of various plasma protein N-glycans are associated with many multifactorial human diseases. Observed associations between protein glycosylation levels and human diseases have led to the conclusion that N-glycans can be considered a potential source of biomarkers and therapeutic targets. Although biochemical pathways of glycosylation are well studied, the understanding of the mechanisms underlying general and tissue-specific regulation of these biochemical reactions in vivo is limited. This complicates both the interpretation of the observed associations between protein glycosylation levels and human diseases, and the development of glycan-based biomarkers and therapeutics. By the beginning of the 2010s, high-throughput methods of N-glycome profiling had become available, allowing research into the genetic control of N-glycosylation using quantitative genetics methods, including genome-wide association studies (GWAS). Application of these methods has made it possible to find previously unknown regulators of N-glycosylation and expanded the understanding of the role of N-glycans in the control of multifactorial diseases and human complex traits. The present review considers the current knowledge of the genetic control of variability in the levels of N-glycosylation of plasma proteins in human populations. It briefly describes the most popular physical-chemical methods of N-glycome profiling and the databases that contain genes involved in the biosynthesis of N-glycans. It also reviews the results of studies of environmental and genetic factors contributing to the variability of N-glycans as well as the mapping results of the genomic loci of N-glycans by GWAS. The results of functional in vitro and in silico studies are described. The review summarizes the current progress in human glycogenomics and suggests possible directions for further research.

The effects of coagulation factors on the risk of endometriosis: a Mendelian randomization study

BackgroundEndometriosis is recognized as a complex gynecological disorder that can cause severe pain and infertility, affecting 6–10% of all reproductive-aged women. Endometriosis is a condition in which endometrial tissue, which normally lines the inside of the uterus, deposits in other tissues. The etiology and pathogenesis of endometriosis remain ambiguous. Despite debates, it is generally agreed that endometriosis is a chronic inflammatory disease, and patients with endometriosis appear to be in a hypercoagulable state. The coagulation system plays important roles in hemostasis and inflammatory responses. Therefore, the purpose of this study is to use publicly available GWAS summary statistics to examine the causal relationship between coagulation factors and the risk of endometriosis.MethodsTo investigate the causal relationship between coagulation factors and the risk of endometriosis, a two-sample Mendelian randomization (MR) analytic framework was used. A series of quality control procedures were followed in order to select eligible instrumental variables that were strongly associated with the exposures (vWF, ADAMTS13, aPTT, FVIII, FXI, FVII, FX, ETP, PAI-1, protein C, and plasmin). Two independent cohorts of European ancestry with endometriosis GWAS summary statistics were used: UK Biobank (4354 cases and 217,500 controls) and FinnGen (8288 cases and 68,969 controls). We conducted MR analyses separately in the UK Biobank and FinnGen, followed by a meta-analysis. The Cochran’s Q test, MR-Egger intercept test, and leave-one-out sensitivity analyses were used to assess the heterogeneities, horizontal pleiotropy, and stabilities of SNPs in endometriosis.ResultsOur two-sample MR analysis of 11 coagulation factors in the UK Biobank suggested a reliable causal effect of genetically predicted plasma ADAMTS13 level on decreased endometriosis risk. A negative causal effect of ADAMTS13 and a positive causal effect of vWF on endometriosis were observed in the FinnGen. In the meta-analysis, the causal associations remained significant with a strong effect size. The MR analyses also identified potential causal effects of ADAMTS13 and vWF on different sub-phenotypes of endometrioses.ConclusionsOur MR analysis based on GWAS data from large-scale population studies demonstrated the causal associations between ADAMTS13/vWF and the risk of endometriosis. These findings suggest that these coagulation factors are involved in the development of endometriosis and may represent potential therapeutic targets for the management of this complex disease.

Short- and Long-Term Stability of Aromatic Amines in Human Urine.

Several aromatic amines (AAs) are established by the International Agency for Research on Cancer as carcinogenic (group 1) or probable/possible carcinogens to humans (group 2A/2B). AAs can be found in mainstream and sidestream smoke from combustible tobacco products, as well as in certain environmental pollution and occupational exposure from several chemical industry sectors. Exposure to AAs can be estimated by measuring their concentrations in urine; however, information about the short-term and long-term stabilities of AAs in urine need to be characterized before conducting large-scale population studies on AA exposure and the potentially harmful effects of AA exposure. In this report, the storage stability of o-toluidine, 2,6-dimethylaniline, o-anisidine, 1-aminonaphthalene, 2-aminonaphthalene, and 4-aminobiphenyl fortified in pooled, filtered, non-smokers' urine is analyzed by isotope dilution gas chromatography-triple quadrupole mass spectrometry (ID GC-MS/MS). The six AAs were measured in urine samples stored at ~20 °C (collection temperature), 4 °C and 10 °C (short-term transit temperatures), and -20 °C and -70 °C (long-term storage temperatures) over a 10-day period. All six analytes were stable for 10 days at transit and long-term storage temperatures but showed reduced recovery at 20 °C. The instability of the target AAs at 20 °C suggests that immediate storage of freshly voided urine at low temperatures is needed to attenuate degradation. A subset of the urine samples was analyzed following a longer storage duration at -70 °C: all AAs were stable for up to 14 months at this temperature. The stability of the six AAs in urine samples can be maintained at the various temperature levels and storage times expected in a typical study set.

Recruitment discrimination of lifetime classic psychedelic users is unjustified: Evidence from employees' motivation-based workplace absenteeism

AbstractBackground and aimsAlthough large-scale population studies have linked the use of classic psychedelics (lysergic acid diethylamide, psilocybin, or mescaline) to reduced odds of physical health problems, mental health problems, and criminal behavior, the roughly 35 million adults in the United States who have used classic psychedelics are nonetheless stigmatized in the American job market. Various federal organizations in the United States automatically reject applicants on the sole basis of prior psychedelic use, thereby practicing an open form of legal discrimination against these applicants. The present study investigates whether this discrimination can be justified based on associations between lifetime classic psychedelic use and motivationally-based workplace absenteeism.MethodsUsing pooled cross-sectional data from the National Survey on Drug Use and Health (2013–2019) on 193,320 employed adults in the United States, this study tests whether lifetime classic psychedelic use predicts the number of workdays employees skipped in the last month (i.e., motivationally-based workplace absenteeism).ResultsAfter adjusting for sociodemographics, physical health indicators, and other substance use, no significant association between lifetime classic psychedelic use and motivationally-based workplace absenteeism is found.ConclusionThis study builds on classic psychedelic research that is just beginning to take work-specific outcomes into account and offers empirical justification for the elimination of arbitrary drug-based recruitment policies in the workplace.

Inflammatory mediators and their special roles in diverse clinical circumstance

The involvement of inflammation is described in all stages of atherosclerosis as well as in dyslipidemias, particularly in lipoproteins (especially oxidized LDL), coronary syndromes, hypertension, diabetes, infections, obesity, and also in the use of sexual replacement hormones. From the first steps of leukocyte recruitment in the nascent atheromatic lesion to the development of atheroma plaque, culminating in its rupture and thrombosis in the acute coronary event, we found a constant release of inflammatory mediators, soluble in plasma, from macrophages, T lymphocytes, endothelial cells and smooth muscle vessels of the vessels, hepatocytes, and adipocytes. The greatest evidence relating inflammation to the future development of cardiovascular events has been verified in large-scale population studies. High concentrations of inflammatory markers such as TNF-α, IL-6, ICAM-1, P-selectin, E-selectin, C Reactive Protein, fibrinogen, and amyloid serum A, in apparently healthy individuals, have shown predictive value for future vascular events. Considering the multifactorial etiology of coronary artery disease and its inflammatory nature, it was possible to find an association between the presence of risk factors and the increase in the concentration of biomarkers of inflammation. TNF-α is a multifunctional cytokine derived from smooth endothelial and muscle cells, as well as macrophages present in the coronary atheroma. It is involved in a number of cardiovascular processes, being increased in congestive heart failure.

Investigating the protective contribution of PLCG2 P522R variant in microglia‐mediated immune pathways in Alzheimer’s Disease

AbstractBackgroundAs the main innate immune cell in central nervous system (CNS), microglia plays an indispensable roles in neuroinflammation and neurodegenerative diseases, such as Alzheimer’s Disease (AD). Large scale population studies have identified an AD‐associated rare coding variant in the Phospholipase C Gamma 2 (PLCG2) locus (rs72824905, P522R, P=5.38x10‐10, odds ratio = 0.68), which potentially offers protection against AD. This variant is associated with lower Aβ1‐42 and pTau181 levels in patients, as well as delays cognitive decline in mild cognitive impairment (MCI) progression. It has been reported that PLCG2 highly expresses in microglia in CNS and mainly involved in immune response, therefore, PLCG2 P522R variant may be a central player in the microglial‐mediated immune pathways during AD pathogenesis.MethodWe generated a PLCG2522R/R knock‐in mouse model carrying this human variant with CRISPR‐mediated gene editing. To explore the protective nature of PLCG2 P522R variant, we generated PLCG2522R/R; 5XFAD mouse model by crossing PLCG2522R/R knock‐in model with the 5XFAD mice, and accessed major AD phenotypes including Aβ load and microgliosis in vivo.ResultOur data showed that PLCG2522R/R;5XFAD mice exhibited attenuated AD pathologies compared with PLCG2522P/P;5XFAD mice, including less burden of Aβ in cortical and hippocampal regions, and less Aβ‐associated microglia clustering around Aβ plaques at early stage of AD.Conclusion PLCG2 P522R variant can protect against AD pathology in PLCG2522R/R;5XFAD mice, which may likely link to its hypermorphic effect in immune pathways, so that PLCG2522R/R microglia potentially have improved phagocytotic function and restrict Aβ accumulation in brain. We believe that investigating the protective role of PLCG2 P522R mutation may help us better understand the neuroinflammation aspect of AD pathogenesis, and provide new strategies to developing clinical therapy in the future.

Abstract IA019: Molecular pathological epidemiology of tumor microbiota and immunity can give etiologic insights

Abstract This lecture discusses the integration of tumor microbiology and immunology into evolving/expanding molecular pathological epidemiology (MPE) research framework (Ogino et al. Gut 2011; Ogino et al. Annu Rev Pathol 2019; Inamura et al. Gut 2022; etc.), which will open new opportunities. Neoplasms represent heterogeneous pathological processes due to interactive influences of the exposome (including the microbiome), the immune system, and neoplastic cells. Hence cancers should be regarded as not only microenvironmental diseases but also environmental and systemic diseases (Inamura et al. Gut 2022). To address this complexity, we investigate influences of exposures on microbial-tumor-immune interactions in tumor microenvironment. Colorectal cancer (CRC) provides an ideal model, as the colorectum is the most microbial rich organ and there are many established or putative risk factors for CRC. In our proof-of-principle studies that used the Nurses’ Health Study and Health Professionals Follow-up Study along with tumor tissue biobanks having 1700 CRC cases, we can provide evidence for influences of prudent diets (Mehta et al. JAMA Oncol 2017), inflammatory diets (Liu et al. Clin Gastroenterol Hepatol 2018), and western diets (Arima et al. Gastroenterology 2022) on developments of cancer subtypes with intratumor bacteria such as Fusobacterium nucleatum and pks+ Escherichia coli. We have also gain insights into interactions between microbes and immune cells. We have discovered an inverse relationship between F. nucleatum and T cell infiltrates (Mima et al. JAMA Oncol 2015), especially CD3+CD4+CD45RO+ memory helper T cells (Borowsky et al. Clin Cancer Res 2021). In situ spatial single cell analyses using multispectral fluorescence imaging and machine learning can shed light on the roles of microbes as well as various immune cell infiltrates in CRC (Vayrynen et al. Cancer Immunol Res 2021; Vayrynen et al. J. ImmunoTher Cancer 2021; Vayrynen et al. Cancer Immunol Res 2022; Akimoto et al. Front Immunol 2022). The integrative MPE approach is also expected to advance research on early-onset cancers (Akimoto et al. Nat Rev Clin Oncol 2021; Ugai et al. Nat Rev Clin Oncol, in press). Our new research paradigm to integrate microbial and immune assays on archival tumor tissue in large-scale population studies can provide not only etiological insights but also possible paths for precision medicine and prevention. Citation Format: Shuji Ogino. Molecular pathological epidemiology of tumor microbiota and immunity can give etiologic insights [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA019.

Primordial Prevention of Atherosclerotic Cardiovascular Disease

The primordial prevention of atherosclerotic cardiovascular disease (ASCVD) involves the prevention of the onset of its risk factors. This review explores the associations between early modifiable risk factors and the development of ASCVD in adulthood, as well as evidence-based interventions to prevent them. A review was conducted on the basis of an in-depth literature search including longitudinal observational data, systematic reviews and meta-analyses published in 2012 or later, clinical trials, and additional manual searches of recent literature based on reference lists of other reviews and relevant guidelines. ASCVD is a disease that begins in childhood; hence, primordial prevention is an important target for improving cardiovascular morbidity and mortality later in life. Data from large-scale population studies have consistently identified the following modifiable risk factors for the development of ASCVD: smoking, overweight and obesity, high cholesterol, high blood pressure, hyperglycemia, poor diet, and physical inactivity. These risk factors originate during the prenatal, childhood, and adolescent stages of life. Various successful interventions to prevent the onset of each risk factor have been evaluated at the individual, community, and population levels. Implementation of a heart-healthy dietary pattern and regular exercise early in life are large components of many successful interventions.

Transient wall shear stress estimation in coronary bifurcations using convolutional neural networks

Background and ObjectiveHaemodynamic metrics, such as blood flow induced shear stresses at the inner vessel lumen, are associated with the development and progression of coronary artery disease. Understanding these metrics may therefore improve the assessment of an individual’s coronary disease risk. However, the calculation of such luminal Wall Shear Stress (WSS) using traditional Computational Fluid Dynamics (CFD) methods is relatively slow and computationally expensive. As a result, CFD based haemodynamic computation is not suitable for integrated and large-scale use in clinical settings. MethodsIn this work, deep learning techniques are proposed as an alternative method to CFD, whereby luminal WSS magnitude can be predicted in coronary bifurcations throughout the cardiac cycle based on the steady state solution (which takes <120 seconds to calculate including preprocessing), vessel geometry and additional global features. The deep learning model is trained on a dataset of 101 patient-specific and 2626 synthetic left main bifurcation models with 26 separate patient-specific cases used as the test set. ResultsThe model showed high fidelity predictions with <5% (normalised against mean WSS magnitude) deviation to CFD derived values as the gold-standard method, while being orders of magnitude faster with on average <2 minutes versus 3 hours computation for transient CFD. ConclusionsThis method therefore offers a new approach to substantially reduce the computational cost involved in, for example, large-scale population studies of coronary haemodynamic metrics, and may therefore open the pathway for future clinical integration.

Association of obstructive sleep apnea and opioids use on adverse health outcomes: A population study of health administrative data.

RationaleDespite the high prevalence of obstructive sleep apnea (OSA) and concurrent use of opioid therapy, no large-scale population studies have investigated whether opioid use and pre-existing OSA may interact synergistically to increase the risk of adverse health consequences. To address this knowledge gap, we conducted a retrospective cohort study using provincial health administrative data to evaluate whether the combined presence of opioid use and OSA increases the risk of adverse health consequences, such as mortality, hospitalizations, and emergency department (ED) visits; and if it does, whether this co-occurrence has synergistic clinical relevance.MethodsWe included all adults who underwent a diagnostic sleep study in Ontario, Canada, between 2013 and 2016. Individuals were considered exposed to opioids if they filled a prescription that overlapped with the date of their sleep study (Opioid+). Individuals with at least a 50% probability of having a diagnosis of moderate to severe OSA (OSA+) were identified using a previously externally validated case-ascertainment model. The primary outcome was all-cause mortality; secondary outcomes were all-cause or ischemic heart disease hospitalizations, all-cause ED visits, and motor vehicle collisions (MVC) requiring hospital or ED visit. We used multivariable Cox regression models to compare hazards between four mutually exclusive groups: (1) Opioid+ OSA+; (2) Opioid+ OSA-; (3) Opioid- OSA+, and (4) OSA- Opioid- (reference for comparison). Relative excess risks due to interaction (RERI) were calculated to test for additive interaction.ResultsOf 300,663 adults who underwent a sleep study, 15,713 (5.2%) were considered as Opioid+ and 128,351 (42.7%) as OSA+. Over a median of two years, 6,223 (2.1%) died from any cause. Regardless of OSA status, opioid use at the date of the sleep study was associated with an increased hazard for all-cause mortality with the greatest hazard associated with Opioid+ OSA- (adjusted hazard ratio [aHR]: 1.75, 95% CI 1.57–1.94), but not Opioid+ OSA+ (aHR: 1.14, 95% CI 1.02–1.27) as hypothesized. Regardless of OSA status, opioid use at the date of the sleep study was associated with an increased hazard for all secondary outcomes. Opioid+ OSA+ was associated with the greatest hazards of all-cause hospitalizations (aHR 1.55, 95% CI 1.49–1.61) and MVC (aHR of 1.39; 95% CI 1.09–1.77); however, no statistically significant synergistic effects were observed.ConclusionsAdults referred for sleep disorder assessment who used opioids had a significantly increased hazard of adverse health outcomes than those who did not, regardless of whether they had a high probability of moderate to severe OSA. The use of opioids and OSA was associated with the greatest hazard of all-cause hospitalizations and MVC requiring hospital or ED visit. The interaction of opioids and OSA did not confer a synergistic risk for poor outcomes.