Coronary artery calcium and risk of chronic kidney disease in young and middle-aged adults.

BACKGROUND: The role of the coronary artery calcium score (CACS) in incident chronic kidney disease (CKD) in asymptomatic young populations remains unclear. The aim of this study was to evaluate the association between CACSs and CKD development in adults. METHODS: A cohort study of 113 171 Korean adults (mean age 40.6 years) without CKD and proteinuria at baseline who underwent a cardiac tomography estimation of CACSs during health screening examinations was performed (median follow-up 4.2 years). The outcome was CKD, defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 and/or the presence of proteinuria. Hazard ratios (HRs) and 95% confidence intervals (CIs) for CKD were estimated using Cox proportional hazards regression analyses. RESULTS: A higher CACS was moderately associated with an increased risk of CKD in a dose-dependent manner. The multivariable-adjusted HRs for CKD comparing CACSs 1-100, 101-300 and >300 with a CACS of 0 were 1.15 (95% CI 1.05-1.25), 1.37 (95% CI 1.13-1.66) and 1.71 (95% CI 1.32-2.22), respectively (P for trend <.001). When CKD was defined using low eGFR and proteinuria separately, corresponding HRs for low eGFR were 1.31 (95% CI 1.05-1.62), 1.41 (95% CI 0.95-2.11) and 1.86 (95% CI 1.16-3.00), respectively (P for trend = .001), while the HRs for proteinuria were 1.11 (95% CI 1.02-1.21), 1.32 (95% CI 1.07-1.64) and 1.57 (95% CI 1.16-2.12), respectively. CONCLUSIONS: A higher CACS was progressively associated with an increased risk of CKD, even at low CACSs. Individuals with a CACS >0 appear to have an increased risk of CKD and may benefit from preventive measures to reduce CKD risk.

The Adverse Effects and Nonmedical Use of Methylphenidate Before and After the Outbreak of COVID-19: Machine Learning Analysis.

BACKGROUND: Methylphenidate is an effective first-line treatment for attention-deficit/hyperactivity disorder (ADHD). However, many adverse effects of methylphenidate have been recorded from randomized clinical trials and patient-reported outcomes, but it is difficult to determine abuse from them. In the context of COVID-19, it is important to determine how drug use evaluation, as well as misuse of drugs, have been affected by the pandemic. As people share their reasons for using medication, patient sentiments, and the effects of medicine on social networking services (SNSs), the application of machine learning and SNS data can be a method to overcome the limitations. Proper machine learning models could be evaluated to validate the effects of the COVID-19 pandemic on drug use. OBJECTIVE: To analyze the effect of the COVID-19 pandemic on the use of methylphenidate, this study analyzed the adverse effects and nonmedical use of methylphenidate and evaluated the change in frequency of nonmedical use based on SNS data before and after the outbreak of COVID-19. Moreover, the performance of 4 machine learning models for classifying methylphenidate use based on SNS data was compared. METHODS: In this cross-sectional study, SNS data on methylphenidate from Twitter, Facebook, and Instagram from January 2019 to December 2020 were collected. The frequency of adverse effects, nonmedical use, and drug use before and after the COVID-19 pandemic were compared and analyzed. Interrupted time series analysis about the frequency and trends of nonmedical use of methylphenidate was conducted for 24 months from January 2019 to December 2020. Using the labeled training data set and features, the following 4 machine learning models were built using the data, and their performance was evaluated using F-1 scores: naïve Bayes classifier, random forest, support vector machine, and long short-term memory. RESULTS: This study collected 146,352 data points and detected that 4.3% (6340/146,352) were firsthand experience data. Psychiatric problems (521/1683, 31%) had the highest frequency among the adverse effects. The highest frequency of nonmedical use was for studies or work (741/2016, 36.8%). While the frequency of nonmedical use before and after the outbreak of COVID-19 has been similar (odds ratio [OR] 1.02 95% CI 0.91-1.15), its trend has changed significantly due to the pandemic (95% CI 2.36-22.20). Among the machine learning models, RF had the highest performance of 0.75. CONCLUSIONS: The trend of nonmedical use of methylphenidate has changed significantly due to the COVID-19 pandemic. Among the machine learning models using SNS data to analyze the adverse effects and nonmedical use of methylphenidate, the random forest model had the highest performance.

Weight Change and the Development of Nonalcoholic Fatty Liver Disease in Metabolically Healthy Overweight Individuals.

INTRODUCTION: The study sought to investigate the effect of weight change on hepatic steatosis (HS) incidence with or without liver fibrosis in metabolically healthy overweight or obese individuals. METHODS: A cohort of 14,779 metabolically healthy men and women who were overweight or obese (body mass index ≥23 kg/m2) and free from HS and an intermediate or high probability of fibrosis at baseline were followed for a median of 5.2 years. Metabolic health was defined as freedom from the components of metabolic syndrome and a homeostatic model assessment of insulin resistance <2.5. Weight changes were calculated as differences from baseline at the next subsequent visit. The outcome was HS incidence, with or without liver fibrosis, as assessed by liver ultrasound and 2 noninvasive fibrosis scores. RESULTS: During 76,794.6 person-years of follow-up, 3539 cases of HS incidence were identified. The multivariable adjusted hazard ratios (95% confidence intervals) for HS incidence by weight change group, <-5.0%, -5.0%-1.0%, 1.0%-5.0%, and >5.0%, relative to the no weight change group (-0.9% to 0.9%) were 0.52 (0.44-0.60), 0.83 (0.75-0.92), 1.21 (1.10-1.33), and 1.51 (1.36-1.69), respectively. Clinically relevant weight loss of >5% was also associated with a lowered risk of HS with intermediate or high probability of advanced fibrosis. In mediation analyses, associations remained significant, although adjustment for metabolic risk factors was attenuating. DISCUSSION: Clinically relevant weight loss was associated with a reduced risk of developing nonalcoholic fatty liver disease with or without intermediate or high probability of advanced fibrosis in metabolically healthy overweight or obese individuals.

Liver fibrosis scores and risk of liver-related mortality in young adults with chronic hepatitis B: A cohort study.

The predictive role of noninvasive liver fibrosis scores on liver-related mortality in patients with chronic hepatitis B below 40 years of age remains unclarified. We examined the association of liver fibrosis scores with liver-related mortality in young (<40 years) and older adults with hepatitis B virus (HBV) infection. A cohort study was performed in 21,360 HBsAg-positive Korean adults without liver cirrhosis or liver cancer at baseline who were followed up for up to 18 years. The liver fibrosis scores were determined using the fibrosis-4 score (FIB-4) and aspartate transaminase to platelet ratio index (APRI). Patients' vital status and cause of death were ascertained through the National Death Records. During a median follow-up of 10.2 years, 283 liver-related deaths were identified (liver-related mortality, 127.4/105 person-years). The liver fibrosis scores were significantly associated with increased risks of liver-related mortality; this association did not differ by age group (<40 vs. ≥40 years). The multivariable-adjusted hazard ratios with 95% confidence intervals for liver-related mortality comparing intermediate and high to low FIB-4 scores were 4.23 (1.99-9.00), and 15.16 (5.18-44.38), respectively, among individuals under 40, and 4.46 (3.03-6.56) and 22.47 (15.11-33.41), respectively, among older individuals. These associations were similar in analyses using APRI. In this cohort of HBsAg-positive individuals, the liver fibrosis scores were associated with increased risks of liver-related mortality in young and older adults. The liver fibrosis scores have a role in predicting liver mortality, even in young adults with HBV.

Fasting Ketonuria and the Risk of Incident Nonalcoholic Fatty Liver Disease With and Without Liver Fibrosis in Nondiabetic Adults.

INTRODUCTION: Dietary carbohydrate restriction or ketogenic diets are known to be beneficial in preventing liver fat accumulation. However, the effect of ketonemia on the risk of nonalcoholic fatty liver disease (NAFLD) in nondiabetic population is largely unknown. We investigated the association between fasting ketonuria and the risk of incident NAFLD in healthy adults. METHODS: A cohort of 153,076 nondiabetic Koreans with no hepatic steatosis and low probability of fibrosis at baseline was followed for a median of 4.1 years. The outcome was incident hepatic steatosis with or without liver fibrosis, and it was assessed by liver ultrasound and noninvasive fibrosis indices, including fibrosis-4 and the NAFLD fibrosis score (NFS). Parametric proportional hazard models were used to estimate hazard ratios (HRs) for outcome according to ketonuria status. RESULTS: Within 677,702.1 person-years of follow-up, 31,079 subjects developed hepatic steatosis. Compared with no ketonuria (reference), fasting ketonuria was significantly associated with a decreased risk of incident hepatic steatosis, with multivariable-adjusted HRs (95% confidence interval) of 0.81 (0.78-0.84). The corresponding HRs for incident hepatic steatosis with intermediate-to-high NFS were 0.79 (0.69-0.90). Similar associations were observed replacing NFS with fibrosis-4. In addition, the presence of persistent ketonuria at both baseline and subsequent visit was associated with the greatest decrease in the adjusted HR for incident NAFLD. DISCUSSION: Ketonuria was associated with a reduced risk of developing incident hepatic steatosis with and without intermediate-to-high probability of advanced fibrosis in a large cohort of nondiabetic healthy individuals. The role of hyperketonemia in the prevention of NAFLD requires further exploration.

Fatty liver disease and changes in dense breasts in pre- and postmenopausal women: the Kangbuk Samsung Health Study.

PURPOSE: While increased breast density is a risk factor for breast cancer, the effect of fatty liver disease on breast density is unknown. We investigated whether fatty liver is a risk factor for changes in breast density over ~ 4 years of follow-up in pre- and postmenopausal women. METHODS: This study included 74,781 middle-aged Korean women with mammographically determined dense breasts at baseline. Changes in dense breasts were identified by more screening mammograms during follow-up. Hepatic steatosis (HS) was measured using ultrasonography. Flexible parametric proportional hazards models were used to determine the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs), and a Weibull accelerated failure time model (AFT) was used to determine the time ratios (TRs) and 95% CIs. RESULTS: During a median follow-up of 4.1 years, 4022 women experienced resolution of the dense breasts. The association between HS and dense breast resolution differed by the menopause status (P for interaction < 0.001). After adjusting for body mass index and other covariates, the aHRs (95% CI) for dense breast resolution comparing HS to non-HS were 0.81 (0.70-0.93) in postmenopausal women, while the association was converse in premenopausal women with the corresponding HRs of 1.30 (1.18-1.43). As an alternative approach, the multivariable-adjusted TR (95% CI) for dense breast survival comparing HS to non-HS were 0.81 (0.75-0.87) and 1.19 (1.06-1.33) in premenopausal and postmenopausal women, respectively. CONCLUSION: The association between HS and changes in dense breasts differed with the menopause status. HS increased persistent dense breast survival in postmenopausal women but decreased it in premenopausal women.

Low Levels of Alcohol Consumption, Obesity, and Development of Fatty Liver With and Without Evidence of Advanced Fibrosis.

BACKGROUND AND AIMS: The effects of low-level alcohol consumption on fatty liver disease and the potential for effect modification by obesity is uncertain. We investigated associations among low-level alcohol consumption, obesity status, and the development of incident hepatic steatosis (HS), either with or without an increase in noninvasive liver fibrosis score category (from low to intermediate or high category). APPROACH AND RESULTS: A total of 190,048 adults without HS and a low probability of fibrosis with alcohol consumption less than 30 g/day (men) and less than 20 g/day (women) were followed for up to 15.7 years. Alcohol categories of no, light, and moderate consumption were defined as 0, 1-9.9, and 10-29.9 g/day (10-19.9 g/day for women), respectively. HS was diagnosed by ultrasonography, and the probability of fibrosis was estimated using the fibrosis-4 index (FIB-4). Parametric proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 43,466 participants developed HS, 2,983 of whom developed HS with an increase in FIB-4 index (to intermediate or high scores). Comparing light drinkers and moderate drinkers with nondrinkers, multivariable-adjusted HRs (95% CI) for incident HS were 0.93 (0.90-0.95) and 0.90 (0.87-0.92), respectively. In contrast, comparing light drinkers and moderate drinkers with nondrinkers, multivariable-adjusted HRs (95% CI) for developing HS plus intermediate/high FIB-4 were 1.15 (1.04-1.27) and 1.49 (1.33-1.66), respectively. The association between alcohol consumption categories and incident HS plus intermediate/high FIB-4 was observed in both nonobese and obese individuals, although the association was stronger in nonobese individuals (P for interaction by obesity = 0.017). CONCLUSIONS: Light/moderate alcohol consumption has differential effects on the development of different stages of fatty liver disease, which is modified by the presence of obesity.

Discordance Between Apolipoprotein B and Low-Density Lipoprotein Cholesterol and Progression of Coronary Artery Calcification in Middle Age.

BACKGROUND: A high level of apolipoprotein B (apoB) is associated with incident coronary artery disease (CAD) when low-density lipoprotein cholesterol (LDL-C) level is discordantly low or concordantly high. However, data on the relationship of apoB with subclinical measure of CAD are limited.Methods and Results:A total of 14,205 men (mean age 41.0 years) who were free of cardiovascular disease at baseline and who underwent a health checkup exam, including measurement of coronary artery calcium (CAC), were studied. Of the study group, 2,773 participants (19.5%) had CAC at baseline, and CAC progression was observed in 2,550 (18.0%). The multivariate-adjusted CAC score ratios (95% confidence interval) comparing discordantly high apoB/low LDL-C and concordantly high apoB/high LDL-C with concordantly low apoB/low LDL-C were 1.51 (0.98-2.32) and 2.70 (2.19-3.33), respectively. The corresponding relative risks for CAC progression were 1.26 (1.02-1.56) and 1.49 (1.34-1.66), respectively. These associations did not change appreciably after adjustment for insulin resistance and subclinical inflammation. CONCLUSIONS: Discordant analysis showed that a high apoB level was strongly associated with prevalence and progression of CAC independent of LDL-C in a large cohort of healthy adults. The present study results highlighted the importance of an apoB measure as a potential target for primary prevention of coronary atherosclerosis in healthy adults.

The prospective relationship between low muscle mass and thyroid hormones among 198 069 euthyroid men and women; comparing different definitions of low muscle mass.

OBJECTIVE: The impact of thyroid hormones within normal range on muscle mass remains unknown. We examined the association between new onset of low muscle mass (LMM) and thyroid hormones among euthyroid men and women with three different definitions of LMM in prospective cohort study. METHODS: We performed a cohort study of 198 069 Korean adults (mean age of 39.2 years), free of LMM at baseline, who participated in a repeated screening examination and were followed up annually or biennially for up to 6.3 years. Thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxin (FT4) levels were measured by an electrochemiluminescent immunoassay. Muscle mass was assessed using a bioelectrical impedance analyser. LMM was defined as the appendicular skeletal muscle mass (ASM) by body weight (ASM/weight, LMM-W), height squared (ASM/height2 , LMM-H) and BMI (ASM/BMI, LMM-B) of one standard deviation below the sex-specific mean for young reference group. RESULTS: During a median follow-up of 3.1 years (interquartile range, 2.0-4.1 years), new-onset LMM-W, LMM-H and LMM-B occurred in 17 856 (incident rate, 27.8 per 1000 person-years), 8307 (incident rate, 13.4 per 1000 person-years) and 13 990 participants (incident rate, 24.5 per 1000 person-years) in each. In euthyroid men, FT4 was inversely and FT3 positively associated with incident LMM-W in a dose-response manner. TSH and FT4 had inverse dose-response relationship with incident LMM-B. Incident LMM-H of euthyroid men has no apparent associations with any thyroid hormones. Euthyroid women had no dose-response relationship between thyroid hormones and any definition of LMM. CONCLUSIONS: Among euthyroid men, FT4 had inverse dose-response association with new onset of LMM defined with weight (LMM-W) and BMI (LMM-B). Height squared LMM (LMM-H) had no apparent relationship with any thyroid hormones. Euthyroid women had no dose-responsive association between thyroid hormones and incident LMM.

Mammographic breast density, its changes, and breast cancer risk in premenopausal and postmenopausal women.

BACKGROUND: The risk of breast cancer related to changes in breast density over time, including its regression and persistence, remains controversial. The authors investigated the relationship between breast density and its changes over time with the development of breast cancer in premenopausal and postmenopausal women. METHODS: The current cohort study included 74,249 middle-aged Korean women (aged ≥35 years) who were free of breast cancer at baseline and who underwent repeated screening mammograms. Mammographic breast density was categorized according to the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS). A dense breast was defined as heterogeneously dense or extremely dense, and changes in dense breasts between baseline and subsequent follow-up were classified as none, developed, regressed, or persistent dense breast. RESULTS: During a median follow-up of 6.1 years (interquartile range, 4.1-8.8 years), a total of 803 incident breast cancers were identified. Baseline breast density was found to be positively associated with incident breast cancer in a dose-response manner, and this association did not significantly differ by menopausal status. The multivariable-adjusted hazard ratios (HRs) for breast cancer comparing "heterogeneously dense" and "extremely dense" categories with the nondense category were 1.96 (95% confidence interval [95% CI], 1.40-2.75) and 2.86 (95% CI, 2.04-4.01), respectively. With respect to changes in dense breasts over time, multivariable-adjusted HRs for breast cancer comparing persistent dense breast with none were 2.37 (95% CI, 1.34-4.21) in premenopausal women and 3.61 (95% CI, 1.78-7.30) in postmenopausal women. CONCLUSIONS: Both baseline dense breasts and their persistence over time were found to be strongly associated with an increased risk of incident breast cancer in premenopausal and postmenopausal women. LAY SUMMARY: Both baseline breast density and its changes over time were found to be independently associated with the risk of breast cancer in both premenopausal and postmenopausal women. The risk of incident breast cancer increased in women with persistent dense breasts, whereas the breast cancer risk decreased as dense breasts regressed. The findings of the current study support that both dense breasts at baseline and their persistence over time are independent risk factors for developing breast cancer.

Alcoholic and Nonalcoholic Fatty Liver Disease and Incident Hospitalization for Liver and Cardiovascular Diseases.

BACKGROUND & AIMS: We compared the associations of nonalcoholic fatty liver disease (NAFLD) and alcohol-associated fatty liver disease (AFLD) with risk of incident hospitalization for liver and cardiovascular diseases. METHODS: We collected data from the Kangbuk Samsung Health Study on 218,030 men and women in Korea who underwent a health examination from 2011 through 2016. Fatty liver disease (FLD) was detected by ultrasound during the initial examination. The Fibrosis-4 index was used to identify individuals with liver fibrosis. Participants were followed up for as long as 5.9 years and data on hospitalizations for liver and cardiovascular diseases were collected. RESULTS: The prevalence of NAFLD was 22.0% and the prevalence of AFLD was 6.4%. Over a median follow-up period of 4.2 years, we observed 51 and 1097 incident cases of liver disease- or cardiovascular disease-related hospitalizations, respectively. After adjustment for potential confounders, the multivariable-adjusted hazard ratios for liver disease-related hospitalization, comparing NAFLD and AFLD with the reference category (no excessive alcohol intake and no FLD), were 1.73 (95% CI, 0.76-3.96) and 5.00 (95% CI, 2.12-11.83), respectively. The corresponding hazard ratios for cardiovascular disease hospitalization were 1.20 (95% CI, 1.02-1.40) and 1.08 (95% CI, 0.86-1.34), respectively. Among participants with FLD, the risk of liver disease-related hospitalization increased with high Fibrosis-4 index scores, whereas the risk of incident cardiovascular disease did not. CONCLUSIONS: In a large cohort study, we found an increased risk of liver disease-related hospitalizations for patients with NAFLD or AFLD, especially among those with Fibrosis-4 index scores. An increased risk of cardiovascular disease-associated hospitalization was observed in patients with NAFLD but not AFLD.

Glycemic Status, Insulin Resistance, and the Risk of Nephrolithiasis: A Cohort Study.

RATIONALE & OBJECTIVE: The effect of glycemic status on nephrolithiasis risk remains controversial. This study sought to examine the association of glycemic status and insulin resistance with incident nephrolithiasis. STUDY DESIGN: A retrospective cohort study. SETTING & PARTICIPANTS: 278,628 Korean adults without nephrolithiasis who underwent a comprehensive health examination between 2011 and 2017. EXPOSURES: Glucose level, glycated hemoglobin level, and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). OUTCOME: Nephrolithiasis ascertained using abdominal ultrasound. ANALYTICAL APPROACH: A parametric proportional hazard model was used to estimate adjusted HRs and 95% CIs. We explored prespecified potential sex differences in the association of glycemic status and incident nephrolithiasis. RESULTS: During a median follow-up of 4.2 years, 6,904 participants developed nephrolithiasis. Associations between levels of glycemic status and incident nephrolithiasis were examined separately in men and women (P for interaction = 0.003). Among men, multivariable-adjusted HRs for incident nephrolithiasis comparing glucose levels of 90-99, 100-125, and ≥ 126 mg/dL were 1.10 (95% CI, 1.01-1.19), 1.11 (95% CI, 1.02-1.21), and 1.27 (95% CI, 1.10-1.46), respectively, while HRs for incident nephrolithiasis comparing glycated hemoglobin levels of 5.7%-5.9%, 6.0%-6.4%, and 6.5%-<5.7% were 1.03 (95% CI, 0.96-1.10), 1.18 (95% CI, 1.07-1.31), and 1.20 (95% CI, 1.06-1.37), respectively. The HR for incident nephrolithiasis comparing the highest HOMA-IR quintile to the lowest quintile was 1.18 (95% CI, 1.06-1.31). Among women, no apparent association was found between glycemic status and nephrolithiasis risk. LIMITATIONS: Glucose tolerance testing and computed tomography assessment for nephrolithiasis were not available. CONCLUSIONS: Higher glycemic values, even within the normoglycemic range, and HOMA-IR were positively associated with increased risk for nephrolithiasis, associations that were only observed among men. Insulin resistance and hyperglycemia may contribute to the development of nephrolithiasis, particularly among men.

Nonheavy Drinking and Worsening of Noninvasive Fibrosis Markers in Nonalcoholic Fatty Liver Disease: A Cohort Study.

The effect of modest alcohol consumption on fibrosis progression in the general population with nonalcoholic fatty liver disease (NAFLD) remains unclear. We examined the association of nonheavy alcohol consumption with worsening of noninvasive fibrosis indices in a large-scale, low-risk population with NAFLD. A cohort study was performed in 58,927 Korean adults with NAFLD and low fibrosis scores who were followed for a median of 4.9 years. Non-, light, and moderate drinkers were defined as 0 g/day, 1-9.9 g/day, and 10-29.9 g/day (10-19.9 g/day for women), respectively. Progression from low to intermediate or high probability of advanced fibrosis was assessed using noninvasive indices including NAFLD fibrosis score (NFS) and Fibrosis-4 Index (FIB-4). A parametric proportional hazards model was used to estimate the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). During 347,925.4 person-years of follow-up, 5,630 subjects with low FIB-4 progressed to intermediate or high FIB-4. The multivariable-adjusted HRs (95% CI) for worsening of FIB-4 comparing light and moderate drinkers with nondrinkers were 1.06 (0.98-1.16) and 1.29 (1.18-1.40), respectively. Similarly, using NFS, corresponding HRs (95% CI) comparing light and moderate drinkers with nondrinkers were 1.09 (1.02-1.16) and 1.31 (1.23-1.40), respectively. Furthermore, the association of moderate drinkers with worsening of either FIB-4 or NFS remained significant after introducing alcohol use and confounders treated as time-varying covariates. Conclusion: In this large-scale cohort of young and middle-aged individuals with NAFLD, nonheavy alcohol consumption, especially moderate alcohol consumption, was significantly and independently associated with worsening of noninvasive markers of fibrosis, indicating that even moderate alcohol consumption might be harmful.

Life's Simple 7 Cardiovascular Health Metrics and Progression of Coronary Artery Calcium in a Low-Risk Population.

Objective- We examined the association of cardiovascular health (CVH) metrics with the development and progression of coronary artery calcium (CAC) among apparently healthy adults. Approach and Results- This cohort study included 65 494 men and women 30 years of age and older free of cardiovascular disease at baseline who underwent a comprehensive exam including CAC scoring. CVH metrics were defined according to the American Heart Association Life's Simple 7 metrics based on smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose. CVH scores range from 0 (all metrics considered unhealthy) to 7 (all metrics considered healthy). Participants were followed-up for a maximum of 6.6 years. Compared with participants with ideal CVH scores 0-1, the multivariable-adjusted difference in the change in geometric means of CAC scores over 5 years of follow-up were -0.40 (-0.62 to -0.19), -0.83 (-1.03 to -0.63), -1.06 (-1.25 to -0.86), -1.22 (-1.42 to -1.03), and -1.05 (-1.42 to -0.69) in participants with ideal CVH scores 2, 3, 4, 5, and 6-7, respectively. The inverse association between CVH scores and progression of CAC was observed both in participants with no CAC and in those with CAC detectable at baseline. Conclusions- A higher ideal CVH metrics score was strongly associated with a lower prevalence of CAC and with lower progression of CAC in males and females in a large cohort of healthy adults. Our findings suggest that maintaining a healthy life habits could help reduce the development and progression of subclinical atherosclerosis and ultimately prevent clinically cardiovascular event.

Epitaxial van der Waals Contacts between Transition-Metal Dichalcogenide Monolayer Polymorphs.

We have achieved heteroepitaxial stacking of a van der Waals ( vdW) monolayer metal, 1T'-WTe2, and a semiconductor, 2H-WSe2, in which a distinctively low contact barrier was established across a clean epitaxial vdW gap. Our epitaxial 1T'-WTe2 films were identified as a semimetal by low temperature transport and showed the robust breakdown current density of 5.0 × 107 A/cm2. In comparison with a series of planar metal contacts, our epitaxial vdW contact was identified to possess intrinsic Schottky barrier heights below 100 meV for both electron and hole injections, contributing to superior ambipolar field-effect transistor (FET) characteristics, i.e., higher FET mobilities and higher on-off current ratios at smaller threshold gate voltages. We discuss our observations around the critical roles of the epitaxial vdW heterointerfaces, such as incommensurate stacking sequences and absence of extrinsic interfacial defects that are inaccessible by other contact methods.

Sequential and Timely Combination of a Cancer Nanovaccine with Immune Checkpoint Blockade Effectively Inhibits Tumor Growth and Relapse.

We describe a small lipid nanoparticle (SLNP)-based nanovaccine platform and a new combination treatment regimen. Tumor antigen-displaying, CpG adjuvant-embedded SLNPs (OVAPEP -SLNP@CpG) were prepared from biocompatible phospholipids and a cationic cholesterol derivative. The resulting nanovaccine showed highly potent antitumor efficacy in both prophylactic and therapeutic E.G7 tumor models. However, this vaccine induced T cell exhaustion by elevating PD-L1 expression, leading to tumor recurrence. Thus, the nanovaccine was combined with simultaneous anti-PD-1 antibody treatment, but the therapeutic efficacy of this regimen was comparable to that of the nanovaccine alone. Finally, mice that showed a good therapeutic response after the first cycle of immunization with the nanovaccine underwent a second cycle together with anti-PD-1 therapy, resulting in suppression of tumor relapse. This suggests that the antitumor efficacy of combinations of nanovaccines with immune checkpoint blockade therapy is dependent on treatment sequence and the timing of each modality.

Alcoholic and non-alcoholic fatty liver disease and associations with coronary artery calcification: evidence from the Kangbuk Samsung Health Study.

OBJECTIVE: Recent evidence suggests that alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD) may differentially affect risk of cardiovascular mortality. To investigate whether early liver disease due to AFLD or NAFLD have similar or dissimilar effects on risk of early coronary artery atherosclerosis, we have investigated the associations between AFLD and NAFLD and coronary artery calcium (CAC). DESIGN: A cross-sectional study was performed in 105 328 Korean adults who attended a health check-up programme. CAC score was assessed using CT, daily alcohol intake was recorded as grams/day and liver fat by ultrasound. Logistic regression model was used to calculate ORs with 95% CIs for prevalent CAC. RESULTS: Both NAFLD and AFLD were positively associated with CAC score. After adjusting for potential confounders, multivariable-adjusted OR (95% CIs) for CAC >0 comparing NAFLD and AFLD to the reference (absence of both excessive alcohol use and fatty liver disease) were 1.10 (95% CI 1.05 to 1.16) and 1.20 (95% CI 1.11 to 1.30), respectively. In post hoc analysis, OR (95% CI) for detectable CAC comparing AFLD to NAFLD was 1.09 (95% CI 1.01 to 1.17). Associations of NAFLD and AFLD with CAC scores were similar in both non-obese and obese individuals without significant interaction by obesity (p for interaction=0.088). After adjusting for homeostasis model assessment of insulin resistance and high-sensitivity C reactive protein, the associations between fatty liver disease and CAC scores remained statistically significant. CONCLUSION: In this large sample of young and middle-aged individuals, early liver disease due to NAFLD and AFLD were both significantly associated with the presence of coronary artery calcification.

Neutrophil-to-lymphocyte ratio and risk of lung cancer mortality in a low-risk population: A cohort study.

Neutrophil-to-lymphocyte ratio (NLR) is associated with poor prognosis in patients with lung cancer, but the predictive role of NLR on the risk of developing lung cancer is unknown. We investigated the association between NLR and lung cancer mortality in lung cancer-free adults. A cohort study was performed with 527,124 Korean adults who were free of lung cancer and were followed for up to 16 years. Vital status and lung cancer-related deaths were ascertained through national death records. Hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer mortality were estimated using a Cox proportional hazards model. During 4,567,495.8 person-years of follow-up, 574 lung cancer deaths were identified. A higher NLR was positively associated with lung cancer mortality. The multivariable-adjusted HR (95% CI) for lung cancer mortality comparing quintiles 2, 3, 4 and 5 of NLR to the lowest quintile were 1.26 (0.96-1.67), 1.23 (0.93-1.63), 1.33 (1.01-1.75) and 1.47 (1.13-1.92), respectively. The highest risk of lung cancer mortality was also observed in the highest NLR quintile among never-smokers and low-risk individuals after adjusting for lung function and other possible confounders. Platelet-to-lymphocyte ratio showed an inverse J-shaped association with lung cancer mortality in men but the trends in women, low-risk individuals or never-smokers were neither linear nor U-shaped. In this large cohort of young and middle-aged individuals, NLR was independently associated with increased risk of lung cancer mortality in low-risk individuals, indicating a role of systemic inflammation in lung cancer mortality in our study population.

Serum concentration of thyroid hormones in abnormal and euthyroid ranges and breast cancer risk: A cohort study.

The impact of variations in serum thyroid hormone concentration within the euthyroid range on breast cancer risk remains unclear. We investigated the effect of serum thyrotropin (TSH) and thyroid hormone concentration on breast cancer risk. This cohort study involved 62,546 Korean women, aged ≥40 years, who were free of breast cancer at baseline and underwent health examination with determination of free thyroxine (FT4) and TSH. A parametric proportional hazard model was used to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI). During a median follow-up of 4.8 years (interquartile range: 2.8-7.3 years), 834 incident breast cancers were identified. Compared to normal FT4 level, abnormally high serum FT4 level was associated with an increased risk of incident breast cancer with a corresponding multivariable aHR (95% CI) of 1.98 (1.02-3.83). This association tended to be stronger in postmenopausal women than in premenopausal women. Within the euthyroid range, the highest TSH tertile was associated with a lower risk of breast cancer than the lowest TSH tertile with a corresponding aHR (95% CI) of 0.68 (0.55-0.84). In contrast, highest FT4 tertile was associated with a higher risk of breast cancer than the lowest FT4 tertile. Abnormally high FT4 as well as higher FT4 within the euthyroid range were positively associated with breast cancer risk, while higher TSH concentration within the euthyroid range was negatively associated with breast cancer risk. Our findings indicate that thyroid function within both the abnormal and euthyroid ranges may contribute to the development of breast cancer.

Obesity and Weight Gain Are Associated With Progression of Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: The effects of weight change on the progression of liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) in the general population are unclear. We evaluated the association of weight change and baseline body mass index (BMI) with fibrosis progression, determined by non-invasive measurement of a marker, in young and middle-aged adults with NAFLD. METHODS: We performed a prospective cohort study of 40,700 adults with NAFLD in Korea who received regular health screening examinations and were followed for a median 6.0 years. Weight change was defined as the difference between weights measured at baseline and at a subsequent follow-up visit. The progression from a low to an intermediate or high probability of advanced fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI). RESULTS: During 275,421.5 person-years of follow-up, 5454 subjects with a low APRI progressed to an intermediate or high APRI. Multivariable-adjusted hazard ratios for APRI progression, determined by comparing the first and second weight change quintiles (the weight-loss group) and the fourth and fifth quintiles (weight-gain group) with the third quintile (weight-stable group, reference), were 0.68 (95% CI, 0.62-0.74), 0.86 (95% CI, 0.78-0.94), 1.17 (95% CI, 1.07-1.28), and 1.71 (95% CI, 1.58-1.85), respectively. The multivariable-adjusted hazard ratios for APRI progression were determined by comparing subjects with BMIs of 23-24.9, 25-29.9, and ≥30 with subjects with BMIs of 18.5-22.9 kg/m2 (reference); these ratios were 1.13 (95% CI, 1.02-1.26), 1.41 (95% CI, 1.28-1.55), and 2.09 (95% CI, 1.86-2.36), respectively. CONCLUSIONS: In a prospective cohort study of 40,700 adults with NAFLD, we found obesity and weight gain to be independently associated with increased risk of fibrosis progression, based on APRI. Maintaining a normal healthy weight and preventing weight gain may help reduce fibrosis progression in individuals with NAFLD.