Neonatal outcomes of preterm infants with pulmonary hypertension: clustering based on prenatal risk factors.

BACKGROUND: To investigate association of prenatal risk factors and neonatal outcomes of preterm infants with pulmonary hypertension (PH). METHODS: A prospective cohort study of very-low-birth-weight infants born at 22-29 weeks' gestation who received PH-specific treatment during hospitalization. Infants were classified using a two-step cluster analysis based on gestational age (GA), small-for-gestational-age (SGA), exposure to antenatal corticosteroids (ACS), histologic chorioamnionitis (HCA), and oligohydramnios. RESULTS: Among 910 infants, six clusters were identified: cluster A (HCA, n = 240), cluster B (oligohydramnios, n = 79), cluster C (SGA, n = 74), cluster D (no-ACS, n = 109), cluster E (no dominant parameter, n = 287), and cluster F (HCA and oligohydroamnios, n = 121). Cluster A was used as a reference group for comparisons among clusters. Compared to cluster A, cluster C (aHR: 1.63 [95% CI: 1.17-2.26]) had higher risk of overall in-hospital mortality. Clusters B (aHR: 1.52 [95% CI: 1.09-2.11]), D (aHR: 1.71 [95% CI: 1.28-2.30]), and F (aHR: 1.51 [95% CI: 1.12-2.03]) had higher risks of receiving PH-specific treatment within the first week of birth compared to cluster A. CONCLUSION: These findings may provide a better understanding of prenatal risk factors contributing to the development of PH. IMPACT: Pulmonary hypertension (PH), presenting as hypoxic respiratory failure, has complex etiologies in preterm infants. Although multifactorial risks for the development of PH in preterm infants are known, few studies have classified infants with similar etiologies for PH. Each cluster has distinct patterns of prenatal condition and neonatal outcome.

Environmental Adaptation of Psychrophilic Bacteria Subtercola spp. Isolated from Various Cryospheric Habitats.

Subtercola boreus K300T is a novel psychrophilic strain that was isolated from permanently cold groundwater in Finland and has also been found in several places in Antarctica including lake, soil, and rocks. We performed genomic and transcriptomic analyses of 5 strains from Antarctica and a type strain to understand their adaptation to different environments. Interestingly, the isolates from rocks showed a low growth rate and smaller genome size than strains from the other isolation sources (lake, soil, and groundwater). Based on these habitat-dependent characteristics, the strains could be classified into two ecotypes, which showed differences in energy production, signal transduction, and transcription in the clusters of orthologous groups of proteins (COGs) functional category. In addition, expression pattern changes revealed differences in metabolic processes, including uric acid metabolism, DNA repair, major facilitator superfamily (MFS) transporters, and xylose degradation, depending on the nutritional status of their habitats. These findings provide crucial insights into the environmental adaptation of bacteria, highlighting genetic diversity and regulatory mechanisms that enable them to thrive in the cryosphere.

Deep Learning for Identifying Promising Drug Candidates in Drug-Phospholipid Complexes.

Drug-phospholipid complexing is a promising formulation technology for improving the low bioavailability of active pharmaceutical ingredients (APIs). However, identifying whether phospholipid and candidate drug can form a complex through in vitro tests can be costly and time-consuming due to the physicochemical properties and experimental environment. In a previous study, the authors developed seven machine learning models to predict drug-phospholipid complex formation, and the lightGBM model demonstrated the best performance. However, the previous study was unable to sufficiently address the degradation of test performance caused by the small size of the training data with class imbalance, and it had the limitation of considering only machine learning techniques. To overcome these limitations, we propose a new deep learning-based prediction model that employs variational autoencoder (VAE) and principal component analysis (PCA) techniques to improve prediction performance. The model uses a multi-layer one-dimensional convolutional neural network (CNN) with a skip connection to effectively capture the complex relationship between drugs and lipid molecules. The computer simulation results demonstrate that our proposed model performs better than the previous model in all performance metrics.

Outcomes in Patients with Pulmonary Arterial Hypertension Underwent Transcatheter Closure of an Atrial Septal Defect.

Pulmonary arterial hypertension (PAH) related to an atrial septal defect (ASD) poses a challenge to transcatheter closure of an ASD (tcASD). We aimed to determine the predictors for remaining PAH (rPAH) post-tcASD. This retrospective study was conducted at a single tertiary university hospital. Adult patients with an ASD and PAH were divided into three groups according to pulmonary vascular resistance (PVR). Normalization of pulmonary atrial systolic pressure (PASP) was defined as an estimated right ventricular systolic pressure < 40 mmHg and was determined using transthoracic echocardiography. Among 119 patients, 80% showed PAH normalization post-tcASD. Normalization of PAH post-tcASD was observed in 100%, 56.2%, and 28.6% of patients in mild, moderate, and severe PVR groups, respectively. The patients' New York Heart Association functional class improved. Multivariate logistic regression analysis showed that age and high PVR were significant risk factors for rPAH. A receiving operator curve analysis showed a PASP cutoff value > 67.5 mmHg to be predictive of rPAH post-tcASD, with an area under the curve value of 0.944 (sensitivity, 0.922; specificity 0.933). Most patients, including moderate-to-severe PAH patients, improved hemodynamically and clinically with tcASD. Since patients with severe PAH are at a risk of rPAH, tcASD should be performed by selecting the patient carefully based on pre-procedure medication, a vasoreactivity test, and a balloon occlusion test.

Relationship between the High Fatty Liver Index and Risk of Fracture.

Background/Aims: The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased rapidly as a consequence of more sedentary lifestyles and a Westernized diet. Fracture is a major clinical problem in older people, but few large-scale cohort studies have evaluated the relationship between NAFLD and fracture. Therefore, we aimed to determine whether the fatty liver index (FLI), which represents the severity of NAFLD, can predict fracture risk. Methods: We analyzed the relationship between the FLI and incident fracture using multivariate Cox proportional hazards models and data for 180,519 individuals who underwent National Health check-ups in the Republic of Korea between 2009 and 2014. Results: A total of 2,720 participants (1.5%) were newly diagnosed with fracture during the study period (median 4.6 years). The participants were grouped according to FLI quartiles (Q1, 0 to <5.653; Q2, 5.653 to <15.245; Q3, 15.245 to <37.199; and Q4 ≥37.199). The cumulative fracture incidence was significantly higher in the highest FLI group than in the lowest FLI group (Q4, 986 [2.2%] and Q1, 323 [0.7%]; p<0.001). The adjusted hazard ratio indicated that the highest FLI group was independently associated with a higher incidence of fracture (hazard ratio for Q4 vs Q1, 2.956; 95% confidence interval, 2.606 to 3.351; p<0.001). FLI was significantly associated with a higher incidence of fracture, independent of the baseline characteristics of the participants. Conclusions: Our data imply that the higher the FLI of a Korean patient is, the higher their risk of osteoporotic fracture, independent of key confounding factors. (Gut Liver, Published online July 27, 2022).

Grabody B, an IGF1 receptor-based shuttle, mediates efficient delivery of biologics across the blood-brain barrier.

Effective delivery of therapeutics to the brain is challenging. Molecular shuttles use receptors expressed on brain endothelial cells to deliver therapeutics. Antibodies targeting transferrin receptor (TfR) have been widely developed as molecular shuttles. However, the TfR-based approach raises concerns about safety and developmental burden. Here, we report insulin-like growth factor 1 receptor (IGF1R) as an ideal target for the molecular shuttle. We also describe Grabody B, an antibody against IGF1R, as a molecular shuttle. Grabody B has broad cross-species reactivity and does not interfere with IGF1R-mediated signaling. We demonstrate that administration of Grabody B-fused anti-alpha-synuclein (α-Syn) antibody induces better improvement in neuropathology and behavior in a Parkinson's disease animal model than the therapeutic antibody alone due to its superior serum pharmacokinetics and enhanced brain exposure. The results indicate that IGF1R is an ideal shuttle target and Grabody B is a safe and efficient molecular shuttle.

Diversity of the Bambusicolous Fungus Apiospora in Korea: Discovery of New Apiospora Species.

Many Apiospora species have been isolated from bamboo plants - to date, 34 bambusicolous Apiospora species have been recorded. They are known as saprophytes, endophytes, and plant pathogens. In this study, 242 bambusicolous Apiospora were isolated from various bamboo materials (branches, culms, leaves, roots, and shoots) and examined using DNA sequence similarity based on the internal transcribed spacer, 28S large subunit ribosomal RNA gene, translation elongation factor 1-alpha, and beta-tubulin regions. Nine Apiospora species (Ap. arundinis, Ap. camelliae-sinensis, Ap. hysterina, Ap. lageniformis sp. nov., Ap. paraphaeosperma, Ap. pseudohyphopodii sp. nov., Ap. rasikravindrae, Ap. saccharicola, and Ap. sargassi) were identified via molecular analysis. Moreover, the highest diversity of Apiospora was found in culms, and the most abundant species was Ap. arundinis. Among the nine Apiospora species, two (Ap. hysterina and Ap. paraphaeosperma) were unrecorded in Korea, and the other two species (Ap. lageniformis sp. nov. and Ap. pseudohyphopodii sp. nov.) were potentially novel species. Here, we describe the diversity of bambusicolous Apiospora species in bamboo organs, construct a multi-locus phylogenetic tree, and delineate morphological features of new bambusicolous Apiospora in Korea.

Seven Unrecorded Indigenous Fungi from Mudeungsan National Park in Korea.

Fungi act as important decomposers in the forest environment. They recycle essential nutrients, promote plant growth through mycorrhizal relationships, and act as food for small animals. Samples of 265 indigenous fungal species were collected from Mudeungsan National Park in 2020. These species were identified based on morphological, molecular, and phylogenetic analyses using the internal transcribed spacer (ITS), nuclear large subunit rRNA (LSU), and RNA polymerase II second largest subunit (rpb2) regions. Subsequently, seven species were identified as unrecorded species in Korea: Cordyceps cicadae, Dentocorticium bicolor, Hymenochaete nanospora, Physisporinus crataegi, Rigidoporus piceicola, Russula raoultii, and Scutellinia crinita. This study reveals their detailed macro- and microscopic morphological characteristics with phylogenetic trees to report them as unrecorded species in Korea.

The impact of non-alcoholic fatty liver disease on sleep apnea in healthy adults: A nationwide study of Korea.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is one of the most common health problems worldwide. Sleep apnea (SA) causes cardiovascular and metabolic problems, as well as a significant socioeconomic burden. Although several studies have found that SA causes NAFLD, there is no evidence that NAFLD causes SA. The goal of this study was to look at the relationship between NAFLD and SA in realworld data. METHODS: We evaluated 334,334 healthy individuals without comorbidities who underwent National Health checkups in the Republic of Korea from 2009 to 2014. NAFLD was defined by a surrogate marker, the fatty liver index (FLI). The association between FLI and SA was analyzed using multivariate Cox proportional hazards regression models. RESULTS: During a median followup of 5.3 years, 1,351 patients (0.4%) were newly diagnosed with SA. Subjects were categorized into quartile groups according to FLI (range: Q1, 0-4.9; Q2, 5.0-12.5; Q3, 12.6-31.0; Q4, >31.0). Subjects with higher FLIs had a significantly higher cumulative incidence of SA than those with lower FLIs (Q1, 119 [0.1%]; Q2, 210 [0.3%]; Q3, 339 [0.4%]; Q4, 683 [0.8%]; P < 0.001). Adjusted hazard ratios (HRs) revealed that a higher FLI was independently associated with an increased risk of SA (HR between Q4 and Q1, 4.03; 95% confidence interval, 3.22-5.05; P < 0.001). This association remained statistically significant after further adjustment for Body mass index (BMI) (HR between Q4 and Q1, 2.19; 95% confidence interval, 1.69-2.83; P < 0.001). FLI was significantly associated with an increased risk of new-onset SA regardless of baseline characteristics. CONCLUSION: This study demonstrated that NAFLD, assessed by FLI, was independently associated with increased risk for SA in the healthy Korean population.

Glaciers as microbial habitats: current knowledge and implication.

Glaciers, formed from the gradual accumulation of snow, can be continuous records representing past environments and recognized as a time capsule of our planetary evolution. Due to extremely harsh conditions, glacial ice has long been considered an uninhabitable ecosystem for microorganisms to sustain their life. However, recent developments in microbiological analysis techniques revealed the presence of unexpectedly diverse microbial strains. Glacial microorganisms could also provide valuable information, including not only biological diversity and structure but also molecular systematics, metabolic profiles, and evolutionary changes from the past climate and ecosystem. However, there are several obstacles in investigating the glacier environment, such as low regional accessibility, technical difficulties of ice coring, potential contamination during the sampling process, and low microbial biomass. This review aims to summarize recent knowledge on decontamination methods, biomass, diversity based on culture-dependent and -independent methods, application of biological proxies, greenhouse gas production and adaptive strategies in glaciers from various regions and to imply further directions for a comprehensive understanding of habitatility in an icy world including outer of our planet.

LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation.

Several preclinical studies demonstrate that antitumor efficacy of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can be improved by combination with other checkpoint inhibitors. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory checkpoint receptor involved in T cell exhaustion and tumor immune escape. Here, we describe ABL501, a bispecific antibody targeting LAG-3 and PD-L1 in modulating immune cell responses against tumors. ABL501 that efficiently inhibits both LAG-3 and PD-L1 pathways enhances the activation of effector CD4+ and CD8+ T cells with a higher degree than a combination of single anti-LAG-3 and anti-PD-L1. The augmented effector T cell responses by ABL501 resulted in mitigating regulatory-T-cell-mediated immunosuppression. Mechanistically, the simultaneous binding of ABL501 to LAG-3 and PD-L1 promotes dendritic cell (DC) activation and tumor cell conjugation with T cells that subsequently mounts effective CD8+ T cell responses. ABL501 demonstrates its potent in vivo antitumor efficacy in a humanized xenograft model and with knockin mice expressing human orthologs. The immune profiling analysis of peripheral blood reveals an increased abundance of LAG-3hiPD-1hi memory CD4+ T cell subset in relapsed cholangiocarcinoma patients after gemcitabine plus cisplatin therapy, which are more responsive to ABL501. This study supports the clinical evaluation of ABL501 as a novel cancer immunotherapeutic, and a first-in-human trial has started (NCT05101109).

Two Unrecorded Apiospora Species Isolated from Marine Substrates in Korea with Eight New Combinations (A. piptatheri and A. rasikravindrae).

Although Apiospora Sacc. has previously been considered a sexual morph of Arthrinium species on the basis of phylogenetic, morphological, and ecological diagnoses, a recent study delimited these as different species. Recently, 14 species, including eight new species, of marine Arthrinium have been reported from Korea. Six known species have previously been renamed as species in the genus Apiospora (A. arundinis, A. marii, A. piptatheri, A. rasikravindrae, A. sacchari, and A. saccharicola). However, the eight new species of marine Arthrinium (Ar. agari, Ar. arctoscopi, Ar. fermenti, Ar. koreanum, Ar. marinum, Ar. pusillispermum, Ar. sargassi, and Ar. taeanense) are yet to be studied, and thus the taxonomic status of these species remains to be clarified. In this study, we conducted phylogenetic analyses using the internal transcribed spacer, 28S large subunit ribosomal RNA gene, translation elongation factor 1-alpha, and beta-tubulin regions to confirm the phylogenetic position of these eight species. Based on these analyses, we re-identified the eight Arthrinium species as new combinations in Apiospora. Additionally, among the six known Apiospora species, two (A. piptatheri and A. rasikravindrae) have not previously been recorded in Korea. On the basis of morphological and molecular analyses, we report these as new species in Korea. Herein, we present scanning electron micrographs detailing the morphologies of these species, along with phylogenetic trees and detailed descriptions.

A nationwide survey of the association between nonalcoholic fatty liver disease and the incidence of asthma in Korean adults.

BACKGROUND: Asthma and nonalcoholic fatty liver disease (NAFLD) are chronic diseases known to be associated with metabolic abnormalities. We aimed to clarify the association between NAFLD and asthma incidence in a large population-based cohort. METHODS AND FINDINGS: We selected 160,603 individuals without comorbidities from the National Health Insurance Service-National Sample cohort between 2009 and 2014. NAFLD was defined using a surrogate marker, fatty liver index (FLI). During a median of 5.08 years' follow-up, 16,377 subjects (10.2%) were newly diagnosed with asthma and categorized into three groups according to FLI. The cumulative incidence of asthma was higher in subjects with higher vs. lower FLIs (FLI < 30, 10.1%; 30 ≤ FLI < 60, 10.8%; FLI ≥ 60, 10.5%). Higher FLI was associated with an increased incidence of asthma (Hazard ratios (HR)highest vs. lowest FLI, 1.25; 95% CI, 1.15-1.36). The results using another definition of NAFLD, as measured by the hepatic steatosis index (HSI), were similar to the primary results. This association was more pronounced in women than in men (HR 1.46; 95% CI, 1.13-1.64 vs. HR 1.07; 95% CI, 0.94-1.20). CONCLUSIONS: This study demonstrated that NAFLD, as measured by FLI and HSI, may influence the incidence rates of asthma in adults, especially in women.

Changes in Archaeal Community and Activity by the Invasion of Spartina anglica Along Soil Depth Profiles of a Coastal Wetland.

Invasion of Spartina spp. in tidal salt marshes may affect the function and characteristics of the ecosystem. Previous studies reported that the invasion alters biogeochemical and microbial processes in marsh ecosystems, yet our knowledge of changing archaeal community due to the invasion is still limited, whereas archaeal communities play a pivotal role in biogeochemical cycles within highly reduced marsh soils. In this study, we aimed to illustrate the influences of the Spartina anglica invasion on soil archaeal community and the depth profile of the influences. The relative abundance of archaeal phyla demonstrated that the invasion substantially shifted the characteristics of tidal salt marsh from marine to terrestrial soil only in surface layer, while the influences indirectly propagated to the deeper soil layer. In particular, two archaeal phyla, Asgardaeota and Diapherotrites, were strongly influenced by the invasion, indicating a shift from marine to terrestrial archaeal communities. The shifts in soil characteristics spread to the deeper soil layer that results in indirect propagation of the influences of the invasion down to the deeper soil, which was underestimated in previous studies. The changes in the concentration of dissolved organic carbon and salinity were the substantial regulating factors for that. Therefore, changes in biogeochemical and microbial characteristics in the deep soil layer, which is below the root zone of the invasive plant, should be accounted for a more accurate illustration of the consequences of the invasion.

Halomonas getboli sp. nov., a halotolerant bacteria isolated from a salt flat.

A novel Gram-stain-negative, rod-shaped, cream-coloured, motile, halotolerant bacterium, designated as YJPS3-2T, was isolated from saltern sediment of the Yellow sea in Yongyu-do, Republic of Korea. Strain YJPS3-2T grew at pH 5.0-10.0 (optimum, pH 7.0), 4-40 °C (optimum, 30 °C) and with 1-15% (w/v) NaCl (optimum 3 %). The 16S rRNA gene sequence analysis indicated that strain YJPS3-2T was closely related to those of Halomonas halophila F5-7T (98.75 %), Halomonas salina F8-11T (98.74 %), Halomonas smyrnensis AAD6T (98.66 %), Halomonas organivorans G-16.1T (98.34 %), Halomonas koreensis SS20T (97.98 %) and Halomonas beimenensis NTU-107T (96.93 %). The average nucleotide identity and digital DNA-DNA hybridization values between YJPS3-2T and related type strains were 86.9-91.6 % and 32.0-44.8 %. Strain YJPS3-2T was characterized as having Q-9 as the predominant respiratory quinone and the principal fatty acids (>10 %) were C16 : 0 (31.4 %), C19 : 0 ω8c cyclo (16.3 %), C17 : 0 cyclo (11.9 %) and C12 : 0 3-OH (10.4 %). The polar lipids consisted of phosphatidylcholine, diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. The DNA G+C content of strain YJPS3-2T is 68.1mol %. Based on the polyphasic taxonomic evidence presented in this study, YJPS3-2T should be classified as representing a novel species within the genus Halmonas, for which name Halomonas getboli is proposed, with the type strain YJPS3-2T (= KCTC 92124T=KACC 22561T=JCM 35085T).

Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade.

BACKGROUND: Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells. METHODS: To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed "ABL503") uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling. RESULTS: Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8+ T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys. CONCLUSION: The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.

Novosphingobium aureum sp. nov., a marine bacterium isolated from salt flat sediment.

A Gram-stain-negative, aerobic, pale yellow-coloured, rod-shaped marine bacterium designated strain YJ-S2-02T was isolated from salt flat sediment sampled in Yongyu-do, Republic of Korea. Strain YJ-S2-02T grew at pH 6.0-9.0 (optimum, pH 7.0), 10-40 °C (optimum, 30 °C) and with optimum 1 % (w/v) NaCl. The 16S rRNA gene sequence analysis indicated that strain YJ-S2-02T was closely related to Novosphingobium naphthalenivorans NBRC 102051T (97.8 %) followed by Novosphingobium mathurense SM117T (97.5 %), Novosphingobium indicum H25T (97.3 %), Novosphingobium pentaromativorans US6-1T (96.8 %), Novosphingobium fontis STM-14T (96.6 %), Novosphingobium endophyticum EGI60015T (96.5 %), Novosphingobium naphthae D39T (96.5 %) and Novosphingobium malaysiense MUSC 273T (95.9 %). The average nucleotide identity and estimated DNA-DNA hybridization values between YJ-S2-02T and related type strains were 77.0-77.9 % and 19.1-24.0 %. Strain YJ-S2-02T was characterized as having Q-10 as the predominant respiratory quinone and the principal fatty acids (>10 %) were summed feature 8 (C18 : 1 ω6c/ω7c, 20.7 %), C18 : 3 ω6c (16.3 %) and C17 : 1 ω6c (11.8 %). The polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids and two unidentified lipids. The DNA G+C content of strain YJ-S2-02T was 65.6 mol%. On the basis of the polyphasic taxonomic evidence presented in this study, YJ-S2-02T should be classified as representing a novel species within the genus Novosphingobium, for which name Novosphingobium aureum is proposed, with the type strain YJ-S2-02T (=KACC 21677T =KCTC 72891T=JCM 33996T).

The genus Arthrinium (Ascomycota, Sordariomycetes, Apiosporaceae) from marine habitats from Korea, with eight new species.

Species of Arthrinium are well-known plant pathogens, endophytes, or saprobes found in various terrestrial habitats. Although several species have been isolated from marine environments and their remarkable biological activities have been reported, marine Arthrinium species remain poorly understood. In this study, the diversity of this group was evaluated based on material from Korea, using morphological characterization and molecular analyses with the internal transcribed spacer (ITS) region, ß-tubulin (TUB), and translation elongation factor 1-alpha (TEF). A total of 41 Arthrinium strains were isolated from eight coastal sites which represented 14 species. Eight of these are described as new to science with detailed descriptions.

Association between nonalcoholic fatty liver disease and cardiovascular disease revealed after comprehensive control of metabolic risk factors: a nationwide population-based study in Korea.

OBJECTIVES: Previous epidemiological studies have limitations in revealing whether cardiovascular disease (CVD) incidence is mediated by interim occurrence of other metabolic diseases in otherwise healthy nonalcoholic fatty liver disease (NAFLD) patients. METHODS: The study population consisted of 334 280 healthy subjects who had had the National Health check-ups in South Korea from 2009 to 2014. The fatty liver index (FLI) was used to identify subjects with NAFLD. CVD was defined as occurrence of a composite of cardiovascular death, myocardial infarction, ischemic stroke, or coronary revascularization. The association between FLI and CVD incidence was analyzed using time-dependent Cox regression analyses. RESULTS: The study population was categorized into quartile groups according to FLI (range: Q1, 0-4.9; Q2, 5.0-12.5; Q3, 12.6-31.0; Q4, >31.0). The median follow-up duration was 5.4 years, during which subjects with higher FLIs experienced CVD more frequently than did those with lower FLIs [Q1, 215 (0.3%); Q2, 498 (0.6%); Q3, 753 (0.9%); Q4, 981 (1.2%); P < 0.001]. Adjustment of baseline characteristics revealed that a higher FLI was independently associated with an increased risk for CVD [hazard ratio between Q4 and Q1, 1.86; 95% confidence interval (CI), 1.59-2.17; P < 0.001]. The association between them remained statistically significant (hazard ratio between Q4 and Q1, 1.92; 95% CI, 1.63-2.25; P < 0.001) after further adjustment for the interim events (diabetes, hypertension, heart failure, and atrial fibrillation). CONCLUSIONS: Otherwise healthy NAFLD patients progressed to develop CVD independently of the interim occurrence of other metabolic diseases, which emphasizes the importance of NAFLD as a potential therapeutic target for prevention of CVD.