S100 Calcium-Binding Protein A9, a Potential Novel Diagnostic Biomarker for Idiopathic Pulmonary Fibrosis.

BACKGROUND: Neutrophilic inflammation is a characteristic feature of idiopathic pulmonary fibrosis (IPF). S100 calcium-binding protein A9 (S100A9) is a neutrophil-derived protein involved in the development of neutrophil-related chronic inflammatory disorders. However, the role of S100A9 in IPF remains unclear. METHODS: We used enzyme-linked immunosorbent assays to measure S100A9 levels in bronchoalveolar lavage fluid (BALF) and serum obtained from healthy controls (HCs) and patients with IPF, non-specific interstitial pneumonia, hypersensitivity pneumonitis, and sarcoidosis. RESULTS: Compared with HCs, BALF S100A9 levels were significantly higher in IPF patients (P < 0.001), patients with hypersensitivity pneumonitis (P = 0.043), and patients with nonspecific interstitial pneumonia (P < 0.001). The S100A9 level in BALF of 0.093 ng/mL could distinguish IPF patients from HCs, with a specificity of 78.8% and a sensitivity of 81.6%. Similarly, the S100A9 level in BALF of 0.239 ng/mL had a specificity of 64.7% and a sensitivity of 66.7% for distinguishing IPF patients from patients with other interstitial lung diseases. Additionally, BALF S100A9 levels were significantly correlated with neutrophil counts (r = 0.356, P < 0.001) in BALF. IPF patients with S100A9 levels in BALF > 0.533 ng/mL had lower survival rates, compared with patients who had levels ≤ 0.553 ng/mL (n = 49; hazard ratio [HR], 3.62; P = 0.021). Combination analysis revealed that IPF patients with S100A9 levels in BALF> 0.553 ng/mL or neutrophil percentages > 49.1% (n = 43) had significantly lower survival rates than patients with S100A9 levels in BALF ≤ 0.553 ng/mL and neutrophil percentages ≤ 49.1% (n = 41) (HR, 3.91; P = 0.014). Additionally, patients with serum S100A9 levels > 0.077 ng/mL (n = 29) had significantly lower survival rates than patients with levels ≤ 0.077 ng/mL (n = 53, HR, 2.52; P = 0.013). S100A9 was expressed on neutrophils and macrophages in BALF from IPF patients as well as α-smooth muscle actin positive cells in the lung tissues. CONCLUSION: S100A9 is involved in the development and progression of IPF. Moreover, S100A9 levels in BALF and serum may be surrogate markers for IPF diagnosis and survival prediction, particularly when analyzed in combination with neutrophil percentages.

Development of a Simple Direct and Hot-Start PCR Using Escherichia coli-Expressing Taq DNA Polymerase.

Taq DNA polymerases have played an important role in molecular biology for several years and are frequently used for polymerase chain reaction (PCR); hence, there is an increasing interest in developing a convenient method for preparing Taq DNA polymerase for routine use in laboratories. We developed a method using Escherichia coli (E. coli) that expresses thermostable Taq DNA polymerase directly in the PCR without purification. The Taq gene was transformed into E. coli and expressed. After overnight incubation and washing, E. coli-expressing Taq DNA polymerase (EcoliTaq) was used as the DNA polymerase without purification. EcoliTaq showed activity comparable to that of commercial DNA polymerase and remained stable for 3 months. With a high-pH buffer containing 2% Tween 20 and 0.4 M trehalose, EcoliTaq facilitated direct PCR amplification from anticoagulated whole blood samples. EcoliTaq exhibited good performance in allele-specific PCR using both purified DNA and whole blood samples. Furthermore, it proved to be useful as a DNA polymerase in hot-start PCR by effectively minimizing non-specific amplification. We developed a simple and cost-effective direct and hot-start PCR method in which EcoliTaq was used directly as a PCR enzyme, thus eliminating the laborious and time-consuming steps of polymerase purification.

The Role of Erythrocyte Membrane Protein Band 4.1-like 3 in Idiopathic Pulmonary Fibrosis.

Novel genetic and epigenetic factors involved in the development and prognosis of idiopathic pulmonary fibrosis (IPF) have been identified. We previously observed that erythrocyte membrane protein band 4.1-like 3 (EPB41L3) increased in the lung fibroblasts of IPF patients. Thus, we investigated the role of EPB41L3 in IPF by comparing the EPB41L3 mRNA and protein expression of lung fibroblast between patients with IPF and controls. We also investigated the regulation of epithelial-mesenchymal transition (EMT) in an epithelial cell line (A549) and fibroblast-to-myofibroblast transition (FMT) in a fibroblast cell line (MRC5) by overexpressing and silencing EPB41L3. EPB41L3 mRNA and protein levels, as measured using RT-PCR, real-time PCR, and Western blot, were significantly higher in fibroblasts derived from 14 IPF patients than in those from 10 controls. The mRNA and protein expression of EPB41L3 was upregulated during transforming growth factor-ß-induced EMT and FMT. Overexpression of EPB41L3 in A549 cells using lenti-EPB41L3 transfection suppressed the mRNA and protein expression of N-cadherin and COL1A1. Treatment with EPB41L3 siRNA upregulated the mRNA and protein expression of N-cadherin. Overexpression of EPB41L3 in MRC5 cells using lenti-EPB41L3 transfection suppressed the mRNA and protein expression of fibronectin and α-SMA. Finally, treatment with EPB41L3 siRNA upregulated the mRNA and protein expression of FN1, COL1A1, and VIM. In conclusion, these data strongly support an inhibitory effect of EPB41L3 on the process of fibrosis and suggest the therapeutic potential of EPB41L3 as an anti-fibrotic mediator.

Synergistic Effect of Saccharin and Caffeine on Antiproliferative Activity in Human Ovarian Carcinoma Ovcar-3 Cells.

The purpose of this study was to confirm the antiproliferative and apoptotic induction potential of a saccharin and caffeine combination in ovarian cancer cells. The cell line used was Ovcar-3, and the cell viability was measured through a WST-8 assay, while a Chou-Talalay assay was used to confirm the synergistic effect of saccharin and caffeine on the ovarian cancer cells. A clonogenic assay, annexin V-FITC/PI-PE double-staining, and RT-PCR were performed to confirm the expression of genes that induce colony formation, cell viability, and apoptosis in ovarian cancer cells treated with the saccharin-caffeine combination. It was demonstrated that both saccharin and caffeine decreased the viability of Ovcar-3 cells, and the cell viability decreased even more significantly when the cells were treated with the combination of saccharin and caffeine. The clonogenic assay results showed that the number of colonies decreased the most when saccharin and caffeine were combined, and the number of colonies also significantly decreased compared to the single-treatment groups. Based on flow cytometry analysis using annexin V-FITC/PI-PE double-staining, it was confirmed that the decrease in cell viability caused by the combination of saccharin and caffeine was correlated with the induction of apoptosis. The results of the RT-PCR confirmed that the combined treatment of saccharin and caffeine promoted cell apoptosis by regulating the expression of apoptosis-inducing genes. These results demonstrate that the combination of saccharin and caffeine more efficiently inhibits the proliferation of Ovcar-3 cells and induces apoptosis in vitro.

Causal Associations Between Serum Bilirubin Levels and Decreased Stroke Risk: A Two-Sample Mendelian Randomization Study.

OBJECTIVE: A number of epidemiological studies have reported that decreased serum bilirubin, an endogenous antioxidant, is associated with cardiovascular disease. However, previous Mendelian randomization analyses conducted using a single sample have shown no evidence of association. Approach and Results: A 2-sample summary Mendelian randomization study was performed by obtaining exposure and outcome data from separate nonoverlapping samples. We utilized data from the KoGES (Korean Genome and Epidemiology Study; n=25 406) and KCPS-II (Korean Cancer Prevention Study-II; n=14 541) biobank for serum bilirubin and stroke, respectively. Using KoGES, a total of 1784 single nucleotide polymorphisms associated with serum bilirubin levels were discovered using a genome-wide significance threshold (P<5×10-8), of which 10 single nucleotide polymorphisms were identified as independent (R2<0.005) and adopted as genetic instruments. From KCPS-II, total and ischemic stroke cases were identified (n=1489 and n=686), with 12 366 acting as controls. Various 2-sample summary Mendelian randomization methods were employed, with Mendelian randomization estimates showing an inverse causal association between serum bilirubin levels and total stroke risk (odds ratio, 0.481 [95% CI, 0.234-0.988]; P=0.046). This association increased in magnitude when restricting the analysis to ischemic stroke cases (odds ratio, 0.302 [95% CI, 0.105-0.868]; P=0.026). CONCLUSIONS: Our findings provide evidence of significant causal relationship between high levels of bilirubin and decreased stroke risk in Korean population in agreement with observational approaches. This highlights the potential for bilirubin to serve as a therapeutic target for oxidative stress-related diseases such as stroke and suggests that previous findings were not a consequence of unmeasured confounding.

Application of material flow analysis for plastic waste management in the Republic of Korea.

The indiscriminate use of plastics and careless management of plastic waste have caused serious environmental challenges globally. The Republic of Korea (ROK) aims to address the issue by reducing plastic waste generation by up to 50%, and increasing recycling rate by up to 70%, by 2030. To determine the status and future directions for plastic waste management in the ROK, the present study undertook two tasks: (i) a material flow analysis of plastic waste material from industrial sectors to assess the current status of plastic waste recycling and treatment, (ii) an analysis of the material flow of plastic waste based on the "Waste Classification Code." According to the findings, 6.202 million metric tons of plastic waste were generated in 2018, out of which 69%, 25%, and 0.5% was recycled, incinerated, and landfilled, respectively. The recycling rate of synthetic resin waste, which accounts for 96% of synthetic waste polymers discharged in the industrial sector, was 69%, which is a very high rate. However, the closed-loop recycling rate was only 33%. Therefore, the system of management of synthetic resin waste discharge without classification of raw materials should be improved to increase the closed-loop recycling rate of synthetic waste polymers. Furthermore, to increase the closed-loop recycling rate, we suggest the subdivision of synthetic resin waste (51-03-01) in plastic waste classification to improve the discharge separation system, which has been mismanaged. Furthermore, we suggest the formulation of a new management strategy for plastic waste, in accordance with those of other hazardous substances, as regulated by the Waste Control Act.

Irreversible effects of long-term chronic smoking on arterial stiffness: An analysis focusing on ex-smokers among otherwise healthy middle-aged men.

Objective: Smoking is a modifiable cardiovascular risk factor closely related to arterial stiffness (AS). However, data are lacking regarding the chronic effects of smoking on AS, especially in ex-smoker (ES) who faces remnant cardiovascular risk when compared to never-smokers (NS).Methods: Among 1722 health screening participants, we retrospectively evaluated 652 healthy men with different smoking history [240 current smoker (CS) vs. 228 ES vs. 184 NS]. To assess AS, augmentation index (AIx), pulse pressure amplification (PPamp), and carotid-femoral pulse wave velocity (cfPWV) were measured and compared.Results: Baseline characteristics were similar except age and triglyceride level. AIx was lowest in NS, followed by ES, and was highest in CS. PPamp was highest in NS, lowest in CS, and ES was of intermediate level. The differences were more robust after adjustment for baseline covariates (AIx, p = 0.005; PPamp: p = 0.001). On the other hand, no significant intergroup difference was observed for cfPWV in our middle-aged population. With the regression analyses revealing an independent association between smoking duration and AS in ES, subgroup analysis demonstrated that long-term ES (smoking duration ≥20 years) had significantly higher AS than short-term ES (<20 years) and NS, approaching levels comparable to CS (AIx and PPamp: p < 0.0001).Conclusions: Our study demonstrated impaired arterial elastic properties in long-term ES, suggesting that AS caused by chronic smoking might be irreversible even after smoking cessation. Further longitudinal studies are warranted to determine the impacts of past smoking on AS and its clinical relevance.

Prevalence of fluoroquinolone-resistant rectal flora in patients undergoing transrectal ultrasound-guided prostate needle biopsy: A prospective multicenter study.

OBJECTIVES: To estimate the prevalence of fluoroquinolone-resistant rectal flora in patients undergoing transrectal ultrasound-guided prostate needle biopsy and to identify the high-risk groups. METHODS: From January 2015 to March 2016, rectal swabs of 557 men who underwent transrectal ultrasound-guided prostate needle biopsy were obtained from five institutions. Clinical variables, including demographics, rectal swab culture results and infectious complications, were evaluated. Univariable and multivariable analyses were used to identify the risk factors for fluoroquinolone resistance of rectal flora and infectious complications. RESULTS: The incidence of fluoroquinolone-resistant and extended-spectrum beta-lactamase production was 48.1 and 11.8%, respectively. The most common fluoroquinolone-resistant bacteria was Escherichia coli (81% of total fluoroquinolone-resistant bacteria, 39% of total rectal flora), and 16 (2.9%) patients had infectious complications. Univariable and multivariable analysis of clinical parameters affecting fluoroquinolone resistance showed no factor associated with fluoroquinolone resistance of rectal flora. The clinical parameter related to infectious complications after prostate biopsy was a history of operation within 6 months (relative risk 6.60; 95% confidence interval 1.99-21.8, P = 0.002). CONCLUSIONS: These findings suggest that a risk-based approach by history taking cannot predict antibiotic resistance of rectal flora, and physicians should consider targeted antibiotic prophylaxis or extended antibiotic prophylaxis for Korean patients undergoing transrectal ultrasound-guided prostate biopsy because of high antibiotic resistance of rectal flora.

Bilirubin and Stroke Risk Using a Mendelian Randomization Design.

BACKGROUND AND PURPOSE: Circulating bilirubin, a natural antioxidant, is associated with decreased risk of stroke. However, the nature of the relationship between the two remains unknown. We used a Mendelian randomization analysis to assess the causal effect of serum bilirubin on stroke risk in Koreans. METHODS: The 14 single-nucleotide polymorphisms (SNPs) (<10-7) including rs6742078 of uridine diphosphoglucuronyl-transferase were selected from genome-wide association study of bilirubin level in the KCPS-II (Korean Cancer Prevention Study-II) Biobank subcohort consisting of 4793 healthy Korean and 806 stroke cases. Weighted genetic risk score was calculated using 14 SNPs selected from the top SNPs. RESULTS: Both rs6742078 (F statistics=138) and weighted genetic risk score with 14 SNPs (F statistics=187) were strongly associated with bilirubin levels. Simultaneously, serum bilirubin level was associated with decreased risk of stroke in an ordinary least-squares analysis. However, in 2-stage least-squares Mendelian randomization analysis, no causal relationship between serum bilirubin and stroke risk was found. CONCLUSIONS: There is no evidence that bilirubin level is causally associated with risk of stroke in Koreans. Therefore, bilirubin level is not a risk determinant of stroke.

FAST: Size-Selective, Clog-Free Isolation of Rare Cancer Cells from Whole Blood at a Liquid-Liquid Interface.

Circulating tumor cells (CTCs) have great potential to provide minimally invasive ways for the early detection of cancer metastasis and for the response monitoring of various cancer treatments. Despite the clinical importance and progress of CTC-based cancer diagnostics, most of the current methods of enriching CTCs are difficult to implement in general hospital settings due to complex and time-consuming protocols. Among existing technologies, size-based isolation methods provide antibody-independent, relatively simple, and high throughput protocols. However, the clogging issues and lower than desired recovery rates and purity are the key challenges. In this work, inspired by antifouling membranes with liquid-filled pores in nature, clog-free, highly sensitive (95.9 ± 3.1% recovery rate), selective (>2.5 log depletion of white blood cells), rapid (>3 mL/min), and label-free isolation of viable CTCs from whole blood without prior sample treatment is achieved using a stand-alone lab-on-a-disc system equipped with fluid-assisted separation technology (FAST). Numerical simulation and experiments show that this method provides uniform, clog-free, ultrafast cell enrichment with pressure drops much less than in conventional size-based filtration, at 1 kPa. We demonstrate the clinical utility of the point-of-care detection of CTCs with samples taken from 142 patients suffering from breast, stomach, or lung cancer.

A prospective Korean multicenter study for infectious complications in patients undergoing prostate surgery: risk factors and efficacy of antibiotic prophylaxis.

This multicenter study was undertaken to determine the efficacy of antibiotic prophylaxis and identify the risk factors for infectious complications after prostate surgery in Korean patients. A total of 424 patients who underwent surgery of the prostate were reviewed. All patients underwent urinalysis and urine culture preoperatively and postoperatively. Efficacy of antibiotic prophylaxis and risk factors for infectious complications were investigated. Infectious complications were observed in 34.9% of all patients. Factors independently associated with infectious complications were diabetes mellitus (adjusted OR, 1.99; 95% CI, 1.09-3.65, P=0.025) and operation time (adjusted OR, 1.08; 95% CI, 1.03-1.13, P=0.004). Clinicians should be aware of the high risk of infectious complications in patients with diabetes and those who undergo a prolonged operation time. Neither the type nor duration of prophylactic antibiotics resulted in differences in infectious complications.

Effects of prostatic inflammation on LUTS and alpha blocker treatment outcomes.

PURPOSE: To evaluate the association between prostatic inflammation and lower urinary tract symptoms (LUTS), and to identify the effects of prostatic inflammation on the treatment with an alpha blocker. MATERIALS AND METHODS: 111 Participants who were aged ≥ 50 years, the presence of LUTS (maximal flow rate < 20 m/s, IPSS ≥ 11), and an elevated PSA level (3-20 ng/mL) were treated with tamsulosin 0.2mg once daily for 3 months after prostate biopsies. Prostatic inflammation was scored as none (0), mild (I), moderate (II), or marked (III). LUTS parameters including urine flow rates, IPSS, PSA, and prostate volume were evaluated. RESULTS: Inflammation grading resulted in 25, 60, and 26 patients that were grade 0, I, and II, respectively. Lower grade inflammation was related to higher urine flow rate at baseline. Patients with higher inflammation grades had larger prostate volumes, larger total and transitional zone volumes, and higher PSA levels. Overall, urine flow rates and residual urine volume were improved after 3 months of alpha blocker therapy. Eighty percent of patients with grade 0 inflammation, 73% of patients with grade I inflammation, and 92.3% of patients with grade II inflammation showed improvement of LUTS after treatment. Longer duration of treatment was related to a decreased chance of improvement of LUTS. Patients with increased IPSS voiding subscales could be predictive of improvement of LUTS. CONCLUSIONS: Patients with high grade inflammation had lower flow rates and higher prostatic volumes than patients with low grade inflammation. Inflammation grade did not affect the outcomes of alpha blocker treatment.

Effect analysis on waste recycling by introducing a new policy, "Environmental Assessment of Recycling," for establishment of the ESG management system in the Republic of Korea.

To move away from linear system mining-manufacture-production-disposal, most countries have been trying to establish a circular economy, by reusing waste as resources. Responding to this paradigm change, the Ministry of Environment of Korea amended the Wastes Control Act in the 2010s. To increase the recycling rate in Korea, the environmental assessment of recycling (EAR) has been introduced to improve the Wastes Control Act. The whole process of new recycling technologies can be assessed in terms of environmental or technical aspects by assessment institutes of the EAR. Finally, the governmental research institute can approve of an application case, which proves environmental friendliness, even if the technology is not defined in the current act. Recently, 17 companies have been coassessed and approved to recycle steel codes in waste tires as resources for iron smelting via assessments of the whole process, such as environmental analysis and quality assessment. The EAR has been enforcing recycling materials for six years, and the total profit of the companies that were approved was estimated to be approximately 55 million USD. However, many amendments to the EAR continue to be requested by stakeholders. In this study, the effect of the EAR was evaluated, and additional tasks were found to enhance the EAR. Integr Environ Assess Manag 2024;00:1-13. © 2024 SETAC.

Aspirin Challenge-Induced Genome-Wide DNA Methylation Profile of Peripheral Blood Lymphocytes in Aspirin-Exacerbated Respiratory Disease.

Genetic variation and epigenetic factors are thought to contribute to the development of hypersensitivity to aspirin. DNA methylation fluctuates dynamically throughout the day. To discover new CpG methylation in lymphocytes associated with aspirin-exacerbated respiratory disease (AERD), we evaluated changes in global CpG methylation profiles from before to after an oral aspirin challenge in patients with AERD and aspirin-tolerant asthma (ATA). Whole-genome CpG methylation levels of peripheral blood mononuclear cells were quantified with an Illumina 860K Infinium Methylation EPIC BeadChip array and then adjusted for inferred lymphocyte fraction (ILF) with GLINT and Tensor Composition Analysis. Among the 866,091 CpGs in the array, differentially methylated CpGs (DMCs) were found in 6 CpGs in samples from all 12 patients with asthma included in the study (AERD, n = 6; ATA, n = 6). DMCs were found in 3 CpGs in the 6 ATA samples and in 615 CpGs in the 6 AERD samples. A total of 663 DMCs in 415 genes and 214 intergenic regions differed significantly in the AERD compared with the ATA. In promoters, 126 CpG loci were predicted to bind to 38 transcription factors (TFs), many of which were factors already known to be involved in the pathogenesis of asthma and immune responses. In conclusion, we identified 615 new CpGs methylated in peripheral blood lymphocytes by oral aspirin challenge in AERD but not in ATA. These findings indicate that oral aspirin challenge induces epigenetic changes in ILFs, specifically in AERD patients, possibly via changes in TF binding, which may have epigenetic effects on the development of AERD.

Adiponectin concentrations: a genome-wide association study.

Adiponectin is associated with obesity and insulin resistance. To date, there has been no genome-wide association study (GWAS) of adiponectin levels in Asians. Here we present a GWAS of a cohort of Korean volunteers. A total of 4,001 subjects were genotyped by using a genome-wide marker panel in a two-stage design (979 subjects initially and 3,022 in a second stage). Another 2,304 subjects were used for follow-up replication studies with selected markers. In the discovery phase, the top SNP associated with mean log adiponectin was rs3865188 in CDH13 on chromosome 16 (p = 1.69 × 10(-15) in the initial sample, p = 6.58 × 10(-39) in the second genome-wide sample, and p = 2.12 × 10(-32) in the replication sample). The meta-analysis p value for rs3865188 in all 6,305 individuals was 2.82 × 10(-83). The association of rs3865188 with high-molecular-weight adiponectin (p = 7.36 × 10(-58)) was even stronger in the third sample. A reporter assay that evaluated the effects of a CDH13 promoter SNP in complete linkage disequilibrium with rs3865188 revealed that the major allele increased expression 2.2-fold. This study clearly shows that genetic variants in CDH13 influence adiponectin levels in Korean adults.

Femoroacetabular cam-type impingement: global assessment of the femoral head-neck junction on a single reformatted MR image.

PURPOSE: To characterize the imaging appearance of femoral head-neck contour abnormalities on a short-axis magnetic resonance (MR) image compared with the usual anterior alpha angle measurements and multiple alpha angle measurements on radial reformatted MR images, with surgery as the reference standard. MATERIALS AND METHODS: After institutional review board approval of this HIPAA-compliant study, 21 patients who underwent arthroscopy and 24 patients who did not, all of whom were evaluated with three-dimensional MR imaging, during 1 year were identified. Short-axis MR images of the femoral head-neck junction were reformatted with multiple radial images along the axis of the femoral neck. The following measurements were made at each hour of a clock face: (a) presence and size of bone contour abnormality visible beyond a best-fit circle and (b) femoral head-neck offset angles. Mann-Whitney, Fisher exact, and Wilcoxon matched-pair signed rank tests were performed. Intra- and interreader agreement were calculated as the Cohen κ. RESULTS: Of the 21 subjects who underwent surgery, 16 were confirmed to have cam-type femoroacetabular impingement (FAI) at surgery. Comparing findings from short-axis images with those at surgery, average accuracy was 81%. Comparing findings from head-neck offset angles with those at surgery, average accuracy was 80%. On short-axis images, average bone elevation was 3.2 mm in patients with cam-type FAI and 1.4 mm in those without it. In eight of 24 subjects who did not undergo surgery, the alpha angle was normal but the short-axis MR image showed abnormal bone contour. CONCLUSION: An abnormal bone contour identified on a short-axis MR image at the femoral head-neck junction correlates with surgical findings and may allow for a global characterization of the bone abnormality with regard to location, extent, and amount of elevation compared with the alpha angle and multiple head-neck offset angles.

Interpretable machine learning to predict adverse perinatal outcomes: examining marginal predictive value of risk factors during pregnancy.

BACKGROUND: The timely identification of nulliparas at high risk of adverse fetal and neonatal outcomes during pregnancy is crucial for initiating clinical interventions to prevent perinatal complications. Although machine learning methods have been applied to predict preterm birth and other pregnancy complications, many models do not provide explanations of their predictions, limiting the clinical use of the model. OBJECTIVE: This study aimed to develop interpretable prediction models for a composite adverse perinatal outcome (stillbirth, neonatal death, estimated Combined Apgar score of <10, or preterm birth) at different points in time during the pregnancy and to evaluate the marginal predictive value of individual predictors in the context of a machine learning model. STUDY DESIGN: This was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be data, a prospective cohort study in which 10,038 nulliparous pregnant individuals with singleton pregnancies were enrolled. Here, interpretable prediction models were developed using L1-regularized logistic regression for adverse perinatal outcomes using data available at 3 study visits during the pregnancy (visit 1: 6 0/7 to 13 6/7 weeks of gestation; visit 2: 16 0/7 to 21 6/7 weeks of gestation; visit 3: 22 0/7 to 29 6/7 weeks of gestation). We identified the important predictors for each model using SHapley Additive exPlanations, a model-agnostic method of computing explanations of model predictions, and evaluated the marginal predictive value of each predictor using the DeLong test. RESULTS: Our interpretable machine learning model had an area under the receiver operating characteristic curves of 0.617 (95% confidence interval, 0.595-0.639; all predictor variables at visit 1), 0.652 (95% confidence interval, 0.631-0.673; all predictor variables at visit 2), and 0.673 (95% confidence interval, 0.651-0.694; all predictor variables at visit 3). For all visits, the placental biomarker inhibin A was a valuable predictor, as including inhibin A resulted in better performance in predicting adverse perinatal outcomes (P<.001, all visits). At visit 1, endoglin was also a valuable predictor (P<.001). At visit 2, free beta human chorionic gonadotropin (P=.001) and uterine artery pulsatility index (P=.023) were also valuable predictors. At visit 3, cervical length was also a valuable predictor (P<.001). CONCLUSION: Despite various advances in predictive modeling in obstetrics, the accurate prediction of adverse perinatal outcomes remains difficult. Interpretable machine learning can help clinicians understand how predictions are made, but barriers exist to the widespread clinical adoption of machine learning models for adverse perinatal outcomes. A better understanding of the evolution of risk factors for adverse perinatal outcomes throughout pregnancy is necessary for the development of effective interventions.

Serum uric acid and chronic kidney disease: the Severance cohort study.

BACKGROUND: Both serum uric acid (SUA) and chronic kidney disease (CKD) are associated with the risk of cardiovascular disease; however, it is unclear whether SUA independently increases the risk of CKD based on longitudinal data. METHODS: To investigate the relationship between SUA levels and CKD development, we initiated a 10.2-year prospective cohort study. Data from 14 939 Koreans, 20-84 years of age, who completed a questionnaire and medical examination at the Severance Health Promotion Center were evaluated. The outcome of interest, CKD, was defined as an estimated glomerular filtration rate (GFR) of <60 mL/min/1.73m(2) via the simplified Modification of Diet in Renal Disease equation. RESULTS: A multivariate Cox proportional hazard model, controlling for age, life style and other cardiovascular risk factors, showed an increased risk of developing CKD for men [hazard ratio (HR) 2.1; 95% confidence interval (CI) 1.6-2.9] and women (HR = 1.3; 95% CI = 1.0-1.8) in the highest quartiles of SUA compared to their counterparts in the lowest quartiles. The relationship between SUA and CKD was linear and stepwise in men. The HRs for renal function Grade 2 (75-89.9 mL/min/1.73m(2)), Grade 3 (60-74.9 mL/min/1.73m(2)) and Grade 4 (<60 mL/min/1.73m(2)) increased with an increase in SUA quartiles as compared to the baseline GFR group (Grade 1, ≥90 mL/min/1.73m(2)). CONCLUSIONS: Higher SUA levels increased the risk of CKD, suggesting that at least part of the reported association between SUA and cardiovascular disease may be connected to CKD.

Role of White Matter Abnormalities in the Relationship Between Microbleed Burden and Cognitive Impairment in Cerebral Amyloid Angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) often presents as cognitive impairment, but the mechanism of cognitive decline is unclear. Recent studies showed that number of microbleeds were associated with cognitive decline. OBJECTIVE: We aimed to investigate how microbleeds contribute to cognitive impairment in association with white matter tract abnormalities or cortical thickness in CAA. METHODS: This retrospective comparative study involved patients with probable CAA according to the Boston criteria (Aß+ CAA) and patients with Alzheimer's disease (Aß+ AD), all of whom showed severe amyloid deposition on amyloid PET. Using mediation analysis, we investigated how FA or cortical thickness mediates the correlation between the number of lobar microbleeds and cognition. RESULTS: We analyzed 30 patients with Aß+ CAA (age 72.2±7.6, female 53.3%) and 30 patients with Aß+ AD (age 71.5±7.6, female 53.3%). The two groups showed similar degrees of cortical amyloid deposition in AD-related regions. The Aß+ CAA group had significantly lower FA values in the clusters of the posterior area than did the Aß+ AD group(family-wise error-corrected p < 0.05). The correlation between the number of lobar microbleeds and visuospatial function was indirectly mediated by white matter tract abnormality of right posterior thalamic radiation (PTR) and tapetum, while lobar microbleeds and language function was indirectly mediated by the abnormality of left PTR and sagittal stratum. Cortical thickness did not mediate the association between lobar microbleeds and cognition. CONCLUSION: This result supports the hypothesis that microbleeds burden leads to white matter tract damage and subsequent cognitive decline in CAA.

Alanine aminotransferase is associated with metabolic syndrome independently of insulin resistance.

BACKGROUND: Few studies have examined the effect of insulin resistance on the association between alanine aminotransferase (ALT) and metabolic syndrome. The association between ALT levels and metabolic syndrome were determined, independently of insulin resistance in Korean populations. METHODS AND RESULTS: The association between ALT and metabolic syndrome were examined in 28,456 subjects who visited 7 Health Promotion Centers at University Hospitals in Korea from 2006 to 2008. HOMA-IR index was used to represent insulin resistance index. ALT levels were found to be positively associated with metabolic syndrome after adjusting for age, alcohol intake, and smoking status. Furthermore, when additional adjustment was made for insulin resistance, this association between ALT and metabolic syndrome, although slightly attenuated, remained strongly significant. Subjects in the highest ALT quartile were found to have a higher risk of having metabolic syndrome than those in the lowest quartile (odds ratio (OR)=4.45, 95% confidence interval (CI)=3.96-4.99 for men and OR=3.51, 95%CI=2.73-4.52 for women). In addition, the association between ALT level and the risk of metabolic syndrome was significantly higher in the relatively low risk group. CONCLUSIONS: ALT levels were found to be significantly associated with metabolic syndrome independently of insulin resistance and with an interaction by age. Further cohort studies are needed to determine the usefulness of ALT levels for predicting the risk of metabolic syndrome.