Purpose: One of the novel cell sources of cell-based liver regenerative medicine is human chemically-derived hepatic progenitors (hCdHs). We previously established this cell by direct hepatocyte reprogramming with a combination of small molecules (hepatocyte growth factor, A83-01, CHIR99021). However, there have been several issues concerning the cell’s stability and maintenance, namely the occurrences of epithelial-mesenchymal transition (EMT) that develop fibrotic phenotypes, resulting in the loss of hepatic progenitor characteristics. These hepatic progenitor attributes are thought to be regulated by SOX9, a transcription factor essential for hepatic progenitor cells and cholangiocytes. Methods: To suppress the fibrotic phenotype and improve our long-term hCdHs culture technology, we utilized the epigenetic modulating drugs DNA methyltransferase inhibitor (5-azacytidine) and histone deacetylase inhibitor (sodium butyrate) that have been reported to suppress and revert hepatic fibrosis. To confirm the essential role of SOX9 to our cell, we used clustered regularly interspaced short palindromic repeats-interference (CRISPRi) to repress the SOX9 expression. Results: The treatment of only 5-azacytidine significantly reduces the fibrosis/mesenchymal marker and EMT-related transcription factor expression level in the early passages. Interestingly, this treatment also increased the hepatic progenitor markers expression, even during the reprogramming phase. Then, we confirmed the essential role of SOX9 by repressing the SOX9 expression with CRISPRi which resulted in the downregulation of several essential hepatic progenitor cell markers. Conclusion These results highlight the capacity of 5-azacytidine to inhibit EMT-driven hepatic fibrosis and the significance of SOX9 on hepatic progenitor cell stemness properties.

Background: Female infertility is a crucial problem with significant implications for individuals and society. In this study, we explore risk factors for infertility in Korean women. Methods: A total of 986 female patients who visited six major infertility clinics in Korea were recruited from April to December 2014. Fertile age-matched controls were selected from two nationwide survey study participants. Conditional logistic regression after age-matching was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of each risk factor for infertility. Results: Women with a body mass index (BMI) < 18.5 kg/m2 had 1.35 times higher odds of infertility (OR, 1.35; 95% CI, 1.03–1.77), while those with a BMI ≥ 25.0 kg/m2 had even higher odds (OR, 2.06; 95% CI, 1.61–2.64) compared to women with a normal BMI (18.5 kg/m2 ≤ BMI < 25 kg/m 2 ). Ever-smokers exhibited 4.94 times higher odds of infertility compared to never-smokers (95% CI, 3.45–8.85). Concerning alcohol consumption, women who consumed ≥ 7 glasses at a time showed 3.13 times significantly higher odds of infertility than those who consumed ≤ 4 glasses at a time (95% CI, 1.79–5.48). Lastly, women with thyroid disease demonstrated 1.44 times higher odds of infertility compared to women without thyroid disease (95% CI, 1.00–2.08). Conclusion Female infertility in Korea was associated with underweight, obesity, smoking, alcohol consumption, and thyroid disease.

Background: As the prevalence of hypertension increases with age and the proportion of the older population is also on the rise, research on the characteristics of older hypertensive patients and the importance of frailty is necessary. This study aimed to identify clinical characteristics of older hypertension in Korea and to investigate these characteristics based on frailty status. Methods: The HOW to Optimize eLDerly systolic BP (HOWOLD-BP) is a prospective, multicenter, open-label, randomized clinical trial that aims to compare intensive (target systolic blood pressure [SBP] ≤ 130 mmHg) with standard (target SBP ≤ 140 mmHg) treatment to reduce cardiovascular events in older hypertensive Korean patients aged ≥ 65 years. Data were analyzed through a screening assessment of 2,085 patients recruited from 11 university hospitals. Demographic, functional (physical and cognitive), medical history, laboratory data, quality of life, and medication history of antihypertensive drugs were assessed. Results: The mean age was 73.2 years (standard deviation ± 5.60), and 48.0% (n = 1,001) were male. Prevalent conditions included dyslipidemia (66.5%), obesity (body mass index ≥ 25 kg/m 2 , 53.6%), and diabetes (28.9%). Dizziness and orthostatic hypotension were self-reported by 1.6% (n = 33) and 1.2% (n = 24), respectively. The majority of patients were on two antihypertensive drugs (48.4%), while 27.5% (n = 574) and 20.8% (n = 433) were on 1 and 3 antihypertensive medications, respectively. Frail to pre-frail patients were older and also tended to have dependent instrumental activities of daily living, slower gait speed, weaker grip strength, lower quality of life, and lower cognitive function. The frail to pre-frail group reported more dizziness (2.6% vs. 1.2%, P < 0.001) and had concerning clinical factors, including lower glomerular filtration rate, more comorbidities such as diabetes, stroke, and a history of admission. Frail to pre-frail older hypertensive patients used slightly more antihypertensive medications than robust older hypertensive patients (1.95 vs. 2.06, P = 0.003). Pre-frail to frail patients often chose beta-blockers as a third medication over diuretics. Conclusion This study described the general clinical characteristics of older hypertensive patients in Korea. Frail hypertensive patients face challenges in achieving positive clinical outcomes because of multifactorial causes: they are older, have more morbidities, decreased function, lower quality of life and cognitive function, and take more antihypertensive medications. Therefore, it is essential to comprehensively evaluate and monitor diseaserelated or drug-related adverse events more frequently during regular check-ups, which is necessary for pre-frail to frail older patients with hypertension.

Purpose: This study aimed to examine the interrupting effect of social distancing (SD) on emergency department (ED) patients with ischemic heart disease (IHD), stroke, asthma, and suicide attempts by PM 2.5 exposure in eight Korean megacities from 2017 to 2020. Materials and Methods: The study used National Emergency Department Information System and AirKorea data. A total of 469014 patients visited EDs from 2017 to 2020. Interrupted time series analysis was employed to examine changes in the level and slope of the time series, relative risk, and confidence intervals (CIs) by PM 2.5 exposure. The SD level was added to the sensitivity analysis. Results: The interrupted time series analysis demonstrated a significant increase in the ratio of relative risk (RRR) of IHD patients in Seoul (RRR=1.004, 95% CI: 1.001, 1.006) and Busan (RRR=1.007, 95% CI: 1.002, 1.012) post-SD. Regarding stroke, only patients in Seoul exhibited a significant decrease post-SD (RRR=0.995, 95% CI: 0.991, 0.999). No significant changes were observed for asthma in any of the cities. In the case of suicide attempts, Ulsan demonstrated substantial pre-SD (RR=0.827, 95% CI: 0.732, 0.935) and post-SD (RRR=1.200, 95% CI: 1.057, 1.362) differences. Conclusion While the interrupting effect of SD was not as pronounced as anticipated, this study did validate the effectiveness of SD in modifying health behaviors and minimizing avoidable visits to EDs in addition to curtailing the occurrence of infectious diseases.

Objectives: This study aimed to identify the psychiatric comorbidity status of adult patients diagnosed with attention-deficit hyperactivity disorder (ADHD) and determine the impact of comorbidities on neuropsychological outcomes in ADHD. Methods: The study participants were 124 adult patients with ADHD. Clinical psychiatric assessments were performed by two boardcertified psychiatrists in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. All participants were assessed using the Mini-International Neuropsychiatric Interview Plus version 5.0.0 to evaluate comorbidities. After screening, neuropsychological outcomes were assessed using the Comprehensive Attention Test (CAT) and the Korean version of the Wechsler Adult Intelligence Scale, Fourth Edition (K-WAIS-IV). Results: Mood disorders (38.7%) were the most common comorbidity of ADHD, followed by anxiety (18.5%) and substance use disorders (13.7%). The ADHD with comorbidities group showed worse results on the Perceptual Organization Index and Working Memory Index sections of the K-WAIS than the ADHD-alone group (p=0.015 and p=0.024, respectively). In addition, the presence of comorbidities was associated with worse performance on simple visual commission errors in the CAT tests (p=0.024). Conclusion These findings suggest that psychiatric comorbidities are associated with poor neuropsychological outcomes in adult patients with ADHD, highlighting the need to identify comorbidities in these patients.

Background/Aims: The optimal systolic blood pressure (SBP) goal for elderly patients with hypertension, especially to reduce cardiovascular disease (CVD) incidence and improve outcome, is unclear. This study aimed to evaluate the beneficial effects of intensive treatment for hypertension on the incidence of CVD in elderly Korean patients. Methods: The HOW to Optimize eLDerly systolic Blood Pressure (HOWOLD-BP) trial is a multicenter, parallel-design, open-label, randomized controlled trial designed to evaluate whether intensive treatment (SBP ≤ 130 mmHg) will provide more benefits in lowering the incidence and mortality associated with CVD than standard treatment (SBP ≤ 140 mmHg) in elderly patients with hypertension aged ≥ 65 years. For this study, eleven university hospitals in Korea will enroll approximately 3,176 elderly patients with hypertension between 2019 and 2022. Patients will be requested to visit the clinic every 4 months for the first year and every 6 months thereafter for 36 months. Parameters, including clinic and home blood pressure, anthropometric and laboratory findings, and frailty assessments, will be collected according to the standardized protocol. The primary outcome is a composite of CVD (acute coronary syndrome, stroke, and heart failure) incidence and cardiovascular deaths. Results: As of December 2021, 1,655 participants had been enrolled in the study, including 831 patients in the standard group and 824 patients in the intensive group. Conclusions The HOWOLD-BP trial is the first study performed in Korea to evaluate the beneficial effects of intensive blood pressure treatment on CVD in elderly patients with hypertension. The results of this study will help clarify the appropriate target SBP for this population.

Background: Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy. Methods: This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years. Conclusion The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.

Objectives: We aimed to examine the association between the relative preference for vegetables and meat and cancer incidence, in a population-based retrospective cohort in Korea. Methods: We included 10,148,131 participants (5,794,124 men; 4,354,007 women) who underwent national health screening between 2004 and 2005 from the National Health Information Database of the National Health Insurance Service (NHIS-NHID). Participants were asked whether they preferred consuming 1) vegetables more often, 2) both vegetables and meat or 3) meat more often. Participants were followed up to Dec. 31, 2017. All cancer and eighteen common cancer cases were identified through the code from the International Classification of Diseases, 10th revision. We estimated sexspecific relative risks and 95% confidence intervals, adjusting for age, body mass index, alcohol consumption, smoking, physical activity, and income level. Results: During an average follow-up of 12.4 years, 714,170 cancer cases were documented. In men, consuming meat more often was associated with lower risk of esophageal, liver, and stomach cancers, but higher risk of lung and kidney cancers. Consuming both vegetables and meat was associated with higher risk of prostate cancer, but with lower risk of esophageal, liver, and stomach cancers in men. In women, consuming meat more often was associated with a higher risk of colorectal cancer and breast, endometrial, and cervical cancers diagnosed before the age of 50. Consuming both vegetables and meat was associated with lower risk of liver cancer in women. Conclusions Our study suggests a potential link between vegetable and meat intake and cancer incidence in the Korean population. Further investigation on the association between the intake of specific types of vegetables and meat and cancer risk in Korean prospective cohort studies is needed.

Background: Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy. Methods: This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years. Conclusion The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.