Intensity of statin therapy and primary prevention of cardiovascular in Korean patients with dyslipidemia.

This study aimed to investigate the association between the intensity of statin therapy and the development of cardiovascular disease (CVD) and diabetes in individuals without prior diabetes who were being treated for dyslipidemia with statins for the primary prevention of CVD, using the National Health Insurance Service-Health Screening database. The database is a longitudinal cohort study of Korean men and women 40 years of age or older who underwent comprehensive biannual screening health examinations by Korean National Health Insurance Service from January 1, 2002, to December 31, 2015. We included patients in the health screening checkup cohort who underwent health checkups in 2009 and 2010.The primary outcome was the occurrence of a first major cardiovascular or cerebrovascular event, new-onset diabetes. A total of 20,322 participants without prior diabetes at baseline from 2009 to 2015 were followed up for a mean duration of 81.2 ±â€…6.6 months. The mean age of all participants at baseline was 59.2 ±â€…8.4 years and 43.0% of them were male. Their index low lipoprotein cholesterol level was 130.4 ±â€…mg/dL, the mean duration of taking statins was 337.4 ±â€…52.3 days, and 93.9% of them had been taking moderate-intensity statins. At that time, a total of 641 diabetes cases occurred, 41 from using low-intensity statins, 588 from moderate-intensity statins, and 11 from high-intensity statins. The results indicated no significant differences in the incidence of death, CVD death, or CVD among those in the strong statin group compared with the reference groups. While statin treatment for the primary prevention of CVD in patients with dyslipidemia showed a subtle difference in the incidence of diabetes, there was no difference in the occurrence of CVD or CVD death according to statin intensity.

Novel small molecule-mediated restoration of the surface expression and anion exchange activity of mutated pendrin causing Pendred syndrome and DFNB4.

Variants in SLC26A4 (pendrin) are the most common reasons for genetic hearing loss and vestibular dysfunction in East Asians. In patients with Pendred syndrome and DFNB4 (autosomal recessive type of genetic hearing loss 4), caused by variants in SLC26A4, the hearing function is residual at birth and deteriorates over several years, with no curative treatment for these disorders. In the present study, we revealed that a novel small molecule restores the expression and function of mutant pendrin. High-throughput screening of 54,000 small molecules was performed. We observed that pendrin corrector (PC2-1) increased the surface expression and anion exchange activity of p.H723R pendrin (H723R-PDS), the most prevalent genetic variant that causes Pendred syndrome and DFNB4. Furthermore, in endogenous H723R-PDS-expressing human nasal epithelial cells, PC2-1 significantly increased the surface expression of pendrin. PC2-1 exhibited high membrane permeability in vitro and high micromolar concentrations in the cochlear perilymph in vivo. In addition, neither inhibition of Kv11.1 activity in the human ether-a-go-go-related gene assay nor cell toxicity in the cell proliferation assay was observed at a high PC2-1 concentration (30 µM). These preclinical data support the hypothesis of the druggability of mutant pendrin using the novel corrector molecule PC2-1. In conclusion, PC2-1 may be a new therapeutic molecule for ameliorating hearing loss and treating vestibular disorders in patients with Pendred syndrome or DFNB4.

Pre-aspirin use has no benefit on the neurological disability and mortality after cardiovascular events: A nation-wide population-based cohort study.

To evaluate the effects of aspirin in the primary prevention, we evaluated disability grades and mortality after ischemic/hemorrhagic stroke and myocardial infarction (MI). A retrospective nation-wide propensity score-matched cohort study was performed using the Korean National Health Information Database. From 3,060,639 subjects who were older than 55 and performed national health examinations in 2004 and 2005, we selected the aspirin group (N = 8770) was composed of patients who had received aspirin prior to cardiovascular events. Cox proportional hazards model was used to compare the acquisition times for neurologic disability grades and survival times between the aspirin and control groups. Only in hemorrhagic stroke, the severe neurologic disability risk was higher in the aspirin group (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.02-1.42). The aspirin group was associated with higher 90-day (HR, 1.33; 95% CI, 1.23-1.44) and long-term mortality risk (HR, 1.06; 95% CI, 1.03-1.10) after pooling 3 events. The old age was a strong risk factor for 90-day mortality in hemorrhagic stroke (50s: reference; 60s: HR 2.21, 95% CI 1.50-3.25; 70s: HR 3.63, 95% CI 2.48-5.30; 80s: HR 6.69, 95% CI 4.54-9.65; >90s: HR 11.28, 95% CI 6.46-19.70). Pre-aspirin use in cardiovascular events has detrimental effects on severe neurological disability in hemorrhagic stroke and short-/long-term mortality in 3 cardiovascular events. The use of aspirin for the primary prevention especially in the elderly should be very cautious because the old age is a strong risk factor for 90-day mortality after hemorrhagic stroke.

The Risk of Major Depressive Disorder Due to Cataracts among the Korean Elderly Population: Results from the Korea National Health and Nutrition Examination Survey (KNHANES) in 2016 and 2018.

Cataracts and major depressive disorder (MDD) both have high prevalence, representing for major health burdens globally. In this study, we examined the risk of MDD due to cataracts. Data from the 2016 to 2018 Korea National Health and Nutrition Examination Survey (KNHANES) were used, including 4122 participants. Logistic regression analysis was performed to evaluate the odds ratio for MDD in association with cataracts. Controlled variables were age, gender, smoking, dyslipidemia and mobility. Subgroup analysis was performed with stratification by gender. The results reveal that cataracts are significantly correlated with MDD. Elderly people with cataracts were found to be more likely to develop MDD compared to those without cataracts (adjusted odds ratio: 1.654; 95% CI = 1.197-2.286). In subgroup analysis, men (adjusted odds ratio: 2.631; 95% CI = 1.247-5.551) were found to be more likely to develop MDD than women (adjusted odds ratio: 1.510; 95% CI = 1.061-2.150). Cataracts may be a risk factor for MDD in the elderly, especially among the male population.

In vivo outer hair cell gene editing ameliorates progressive hearing loss in dominant-negative Kcnq4 murine model.

Outer hair cell (OHC) degeneration is a major cause of progressive hearing loss and presbycusis. Despite the high prevalence of these disorders, targeted therapy is currently not available. Methods: We generated a mouse model harboring Kcnq4W276S/+ to recapitulate DFNA2, a common genetic form of progressive hearing loss accompanied by OHC degeneration. After comprehensive optimization of guide RNAs, Cas9s, vehicles, and delivery routes, we applied in vivo gene editing strategy to disrupt the dominant-negative allele in Kcnq4 and prevent progressive hearing loss. Results:In vivo gene editing using a dual adeno-associated virus package targeting OHCs significantly improved auditory thresholds in auditory brainstem response and distortion-product otoacoustic emission. In addition, we developed a new live-cell imaging technique using thallium ions to investigate the membrane potential of OHCs and successfully demonstrated that mutant allele disruption resulted in more hyperpolarized OHCs, indicating elevated KCNQ4 channel activity. Conclusion: These findings can facilitate the development of targeted therapies for DFNA2 and support the use of CRISPR-based gene therapy to rectify defects in OHCs.

Metformin and Cervical Cancer Risk in Patients with Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea.

BACKGRUOUND: Cervical cancer is a prevalent malignancy that is a major health problem for women worldwide. The cancer-preventive properties of metformin are well-known, but insufficient data have been reported regarding its relationship to cervical cancer. Therefore, in a nationwide population-based study, we investigated the association between metformin use and cervical cancer incidence in patients with newly diagnosed type 2 diabetes. METHODS: This retrospective cohort study used the Korean National Health Insurance claims database. Individuals newly diagnosed with type 2 diabetes between January 2005 and December 2009 were included. The occurrence of cervical cancer was explored by matching for age, economic status, region of residence, and use of anti-diabetic medication. RESULTS: In total, 66,013 metformin users and 64,756 non-users were analyzed. Cervical cancer occurred in 219 metformin users (0.33%) and 274 metformin non-users (0.42%) (hazard ratio [HR], 0.783; 95% confidence interval [CI], 0.655 to 0.036; P=0.007). Moreover, cervical cancer risk was considerably reduced in those treated with a high dose (>1,200,000 mg) or for an extended period (≥2,000 days) compared to non-users (HR, 0.151; 95% CI, 0.093 to 0.243; P<0.001; and HR, 0.141; 95% CI, 0.077 to 0.258; P<0.001). The incidence was also significantly lower in metformin users among those over 50 years old (HR, 0.791; 95% CI, 0.650 to 0.961; P<0.001). CONCLUSION: Metformin use in patients with newly diagnosed diabetes was associated with a lower risk of cervical cancer in Korea. Furthermore, a significant association was found between the use of metformin and cervical cancer in a dose- and duration-dependent manner and among those over 50 years old.

Mechanical thrombectomy reduces the gap in treatment outcomes of ischemic stroke between hospital levels of care: analysis of a Korean nationwide data.

BACKGROUND: Mechanical thrombectomy (MT) of ischemic stroke was demonstrated to be effective in clinical trials and was reported to have favorable outcomes in real clinical settings since 2015. We aimed to determine the national trends of MT and compare the outcomes between the different levels of treating hospital. METHODS: We obtained data from the nationwide database from 2008 to 2017. Patients with ischemic stroke who received MT were identified using the International Classification of Disease Codes. Good outcome was defined as discharge to home, and a poor outcome was defined as cerebral hemorrhage, physical disability, or death. The study period was divided into three (off-label MT, transitional, MT period). Hospital groups where MT was performed were divided into tertiary and non-tertiary hospitals. RESULTS: In MT period, 47.0% of the MT procedures were performed in non-tertiary hospitals compared with 36.1% in off-label MT period. Comparison of the 3-month mortality between patients who were treated in tertiary vs. non-tertiary hospitals revealed significant lower mortality in tertiary hospital through all period. The incidence of cerebral hemorrhage and physical disability did not differ between hospital groups. However, the percentage of patients discharged home was 41.4% for tertiary hospitals and 42.4% for non-tertiary hospitals, which was not statistically different in MT period (P=0.4671). CONCLUSIONS: Analysis of the nationwide data confirmed that the extent of increase in MT was higher in non-tertiary hospitals than tertiary hospitals. In addition, no significant difference was revealed in the number of favorable clinical outcome between the hospital groups during MT period.

A nationwide population-based study of incidence and mortality of lung cancer in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an independent risk factor for lung cancer (LC) development; however, there are currently no clinical guidelines for LC surveillance in IPF. This study aimed to investigate the cumulative incidence and survival outcomes of LC in IPF. Using the National Health Insurance Service database, including medical information on people aged ≥ 40 years between 2011 and 2016, we identified IPF patients and confirmed the presence of comorbid LC. Patients diagnosed with IPF in 2011 were washed out, and mortality data were analyzed from 2012 to 2018. A total of 7277 newly diagnosed IPF patients were identified among Korean citizens aged ≥ 40 years (about 50 million people) between 2011 and 2016. Their average age was 71.5 years and 72.8% of them were male. The prevalence of LC in the IPF cases was 6.4%. The cumulative incidence rates of LC in IPF patients who did not have LC at the time of IPF diagnosis were 1.7%, 4.7%, and 7.0%, at 1, 3, and 5 years, respectively. The median time from IPF diagnosis to LC development was 16.3 (Interquartile range, 8.2-28.8) months. The survival rate was significantly lower in the IPF with LC group than the IPF without LC group (P < 0.001). We concluded that IPF increases LC risk, and LC weakens survival outcomes in IPF. Close surveillance for LC development is mandatory for patients with IPF.

Relationship between the type of hormone replacement

Objective@#After Women's Health Initiative (WHI) trial, hormone replacement therapy (HRT) prescription rate dropped by 16% in Korea. We investigated the relationship between the type of HRT and incidence of breast cancer (BC) in postmenopausal women in Korea.Material & Methods: We compared the prevalence of BC in 356,160 women on HRT, who reached menopause between 2004 and 2007. We divided the type and duration of HRT into three categories, i.e., estrogen-progestogen therapy (EPT), estrogen-only therapy (ET), tibolone, and 1– 3 years, 3–5 years, and ＞5 years, respectively. @*Results@#Regarding the type of HRT among all age groups, BC risk (BCR) was lower in the tibolone group (P＜0.01). Based on age group, BCR was lower in the 50–59 years group using EPT (P=0.03) and tibolone (P＜0.01). HRT administration for ＜3 years showed a significant decrease in the tibolone group (P=0.04) and an increase in the ET group (P=0.03). In groups undergoing HRT for ＞5 years, BCR in all groups decreased (P＜0.05). @*Conclusions@#The results suggest that tibolone reduces the risk of BC in women aged ≥50 years and HRT use for ≥5 years was related to significantly decreased BCR in Korea.

Effects of BMI and LDL-cholesterol change pattern on cardiovascular disease in normal adults and diabetics.

INTRODUCTION: To examine how the risk of cardiovascular disease changes according to degree of change in body mass index (BMI) and low-density lipoprotein (LDL)-cholesterol in patients with diabetes using the health medical examination cohort database of the National Health Insurance Service in Korea. In comparison, the pattern in a non-diabetic control group was also examined. RESEARCH DESIGN AND METHODS: The study samples were 13 800 patients with type 2 diabetes and 185 898 non-diabetic controls, and their baseline characteristics and repeatedly measured BMI and LDL-cholesterol until occurrence of cardiovascular disease were collected in longitudinal data. We used the variability model that is joint of mixed effects and regression model, then estimated parameters about variability by Bayesian methods. RESULTS: The risk of cardiovascular disease was increased significantly with high average real variability (ARV) of BMI in the patients with diabetes, but the risk of cardiovascular disease was not increased according to degree of ARV in non-diabetic controls. The Bayesian variability model was used to analyze the effects of BMI and LDL-cholesterol change pattern on development of cardiovascular disease in diabetics, showing that variability did not have a statistically significant effect on cardiovascular disease. This shows the danger of the former simple method when interpreting only the mean of the absolute value of the variation. CONCLUSIONS: The approach of simple SD in previous studies for estimation of individual variability does not consider the order of observation. However, the Bayesian method used in this study allows for flexible modeling by superimposing volatility assessments on multistage models.

Metformin and Gastrointestinal Cancer Development in Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea.

INTRODUCTION: Clinical studies have produced conflicting results on the effects of metformin on gastrointestinal cancer development. We aimed to investigate the association between metformin use and stomach, colon, liver, and pancreatic cancer development among patients with newly diagnosed, drug-naïve type 2 diabetes. METHODS: This retrospective study evaluated propensity score-matched patients with newly diagnosed type 2 diabetes from the Korean National Health Insurance Service database. Metformin users were categorized into tertiles according to the cumulative dose or duration of metformin treatment, and the risks of gastrointestinal cancers were compared. RESULTS: Metformin users had reduced risks of developing stomach cancer (hazard ratio [HR]: 0.841, 95% confidence interval [CI]: 0.797-0.887), colon cancer (HR: 0.865, 95% CI: 0.822-0.91), and liver cancer (HR: 0.709, 95% CI: 0.675-0.746; P < 0.001). However, metformin users did not have a reduced overall risk of pancreatic cancer (HR: 1.335, 95% CI: 1.209-1.475; P < 0.001). The risks tended to decrease at higher cumulative doses and durations of metformin use, with significantly reduced risks of all 4 cancers at the highest cumulative dose (≥1,200,000 mg) and the longest duration (≥2,000 days) of metformin use. DISCUSSION: This population-based data suggest that metformin could be associated with reductions in the risks of stomach, colon, and liver cancers, as well a reduced risk of pancreatic cancer in some subgroups. Metformin has benefit as a first-line treatment for type 2 diabetes mellitus. A further role in cancer risk reduction could be studied in controlled trials.

Prevalence, incidence, and mortality of nontuberculous mycobacterial infection in Korea: a nationwide population-based study.

BACKGROUND: Epidemiologic characteristics of nontuberculous mycobacterial (NTM) disease remain largely unknown. The objective of this study was to evaluate incidence, prevalence, and mortality of NTM infection in a large nationwide population-based cohort in Korea. METHODS: Data of the National Health Insurance Service database, an extensive health-related database including most Korean residents, were used. Adults with a primary diagnosis of NTM as determined by International Classification of Disease-Tenth Revision coding (A31) were identified between 2003 and 2016. Incidence, prevalence, and mortality of NTM infection were analyzed. RESULTS: A total of 46,194 individuals had a primary diagnosis of NTM infection. Their mean age was 55.8 years. Of these subjects, 61.1% were females. Annual age-adjusted incidence and prevalence of NTM infection tended to increase rapidly from 2003 to 2016. Age-adjusted incidence and prevalence was 17.9 and 33.3 per 100,000 population in 2016. The incidence and prevalence were higher in females and the elderly. The 5-year mortality rate in the population with NTM infection was 17.8%. The standardized mortality ratio of patients with NTM infection to the general population was 2.16 (95% confidence interval: 2.10 to 2.22). CONCLUSIONS: This large population-based study showed that the incidence and prevalence of NTM infection in Korea increased rapidly from 2003 to 2016. They were higher in women and the elderly. The mortality rate in the population with NTM infection was higher than that in the general population.

The effect of missing teeth on dementia in older people: a nationwide population-based cohort study in South Korea.

BACKGROUND: To determine the effect of missing teeth on the risk of dementia onset among individuals who received tooth extractions and those who did not, based on the number of missing teeth. METHODS: We selected individuals who had not been diagnosed or treated for dementia between 2002 to 2011 from the National Health Insurance Service-Elderly Cohort Database (NHIS-ECD). We divided participants into two cohorts, a tooth extraction and non-extraction cohort, based on tooth loss from 2002 to 2011. After propensity score matching, there were 104,903 individuals in each cohort, and we included a total of 209,806 individuals in this study. Each cohort was grouped by sex, age, residential area, health insurance eligibility, income level, history of dental caries, history of periodontal treatment, and number of extracted teeth. We analyzed the relationship between dementia onset and these variables using logistic regression analysis. RESULTS: Individuals with tooth loss had a higher risk for dementia than those without tooth loss (odds ratio [OR] = 1.18; 95% confidence interval [CI]: 1.146-1.215). Regarding the incidence of dementia, the OR increased as the number of missing teeth and age increased, and the OR was higher for women (OR = 1.33; 95% CI: 1.286-1.367) than for men, and this difference was statistically significant (P < 0.01). The incidence of dementia decreased with periodontal treatment (OR = 0.96; 95% CI: 0.932-0.992) and increased with dental caries (OR = 1.07; 95% CI: 1.035-1.101). CONCLUSIONS: These results suggest that it is important to delay tooth loss and preserve the stable remaining teeth to help prevent dementia.

Protective Effect of Metformin Against Thyroid Cancer Development: A Population-Based Study in Korea.

BACKGROUND: Metformin, the most widely used drug for type 2 diabetes, has recently attracted attention with regard to its antitumor activity. However, clinical studies have yielded conflicting results regarding the association between metformin and thyroid cancer development, despite its antitumor effect in preclinical studies. METHODS: This is a retrospective cohort study using the Korean National Health Insurance claim database. Matched populations of 128,453 metformin users and 128,453 non-users were analyzed for thyroid cancer incidence. Metformin users were categorized into lowest, middle, and highest tertiles according to cumulative dose or duration of metformin therapy. RESULTS: Thyroid cancer developed in 340 (0.26%) metformin users and 487 (0.38%) non-users during a mean follow-up of 7.2 years (hazard ratio = 0.69 [confidence interval 0.60-0.79]; p < 0.001). The incidence of thyroid cancer per 105 person-years was 51.6 in metformin non-users. For metformin users, the incidence was 84.5 for <529,000 mg, 20.6 for 529,000-1,007,799 mg, and 6.3 for >1,007,799 mg; 86.3 for <1085 days, 20.3 for 1085-2094 days, and 4.7 for >2094 days for duration of therapy. The hazard ratio for thyroid cancer decreased significantly in metformin users as a function of dose and duration of metformin therapy. CONCLUSIONS: Metformin appears to be associated with a preventive effect on thyroid cancer development in a nationwide population-based study, but is not effective in the early phase of treatment. Considering the increasing prevalence of obesity and the role of insulin resistance in the development of cancer, metformin might be the preferred treatment for its dual anti-diabetic and antitumor effects.

Prevalence, incidence, and mortality of sarcoidosis in Korea, 2003-2015: A nationwide population-based study.

BACKGROUND: The prevalence and incidence of sarcoidosis, a granulomatous disorder involving multiple organ systems, varies among geographical regions and ethnicities. This study evaluated the incidence, prevalence, and mortality of sarcoidosis in a large nationwide population-based cohort in Korea. METHODS: We used data of the National Health Insurance Service database, which is an extensive health-related database including most Korean residents. Adults with a primary diagnosis of sarcoidosis, as determined by International Classification of Disease-Tenth Revision coding (D86), were identified between 2003 and 2015. The incidence, prevalence, and mortality of sarcoidosis were analysed by sex and age. RESULTS: A total of 6376 individuals had a primary diagnosis of sarcoidosis. Their mean age was 48.8 years, and 58.6% were women. The age-adjusted incidence and prevalence of sarcoidosis were 1.3 and 3.4 per 100,000 population respectively; both tended to increase between 2003 and 2015. The all-cause mortality rate was 13.1 per 1000 sarcoidosis patients. The standardised mortality ratio of sarcoidosis patients to the general population was 1.7 (95% confidence interval, 1.5 to 1.8). CONCLUSIONS: This is the largest epidemiologic study of sarcoidosis in an Asian population to date. In Korea, the annual incidence and prevalence of sarcoidosis were relatively low but tended to increase over the 13 years of the study period. Importantly, the overall mortality rate of patients with sarcoidosis was higher than that of the general population.

Functional chromatography reveals three natural products that target the same protein with distinct mechanisms of action.

Access to lead compounds with defined molecular targets continues to be a barrier to the translation of natural product resources. As a solution, we developed a system that uses discrete, recombinant proteins as the vehicles for natural product isolation. Here, we describe the use of this functional chromatographic method to identify natural products that bind to the AAA+ chaperone, p97, a promising cancer target. Application of this method to a panel of fungal and plant extracts identified rheoemodin, 1-hydroxydehydroherbarin, and phomapyrrolidone A as distinct p97 modulators. Excitingly, each of these molecules displayed a unique mechanism of p97 modulation. This discovery provides strong support for the application of functional chromatography to the discovery of protein modulators that would likely escape traditional high-throughput or phenotypic screening platforms.

Culture Conditions for Mycelial Growth of Coriolus versicolor.

Coriolus versicolor, is one of the most popular medicinal mushrooms due its various biologically active components. This study was conducted to obtain basic information regarding the mycelial culture conditions of C. versicolor. Based on the culture, and MCM media were suitable for the mycelial growth of the mushroom. The optimum carbon and nitrogen sources were dextrin and yeast extract, respectively, and the optimum C/N ratio was 10 to 2 when 2% glucose was used. Other minor components required for optimal growth included thiamine-HCl and biotin as vitamins, succinic acid, lactic acid and citric acid as organic acids, as well as MgSO4·7H2O as mineral salts.

Isolation and characterization of rpoS from a pathogenic bacterium, Vibrio vulnificus: role of sigmaS in survival of exponential-phase cells under oxidative stress.

A gene homologous to rpoS was cloned from a fatal human pathogen, Vibrio vulnificus. The functional role of rpoS in V. vulnificus was accessed by using an rpoS knockout mutant strain. This mutant was impaired in terms of the ability to survive under oxidative stress, nutrient starvation, UV irradiation, or acidic conditions. The increased susceptibility of the V. vulnificus mutant in the exponential phase to H2O2 was attributed to the reduced activity of hydroperoxidase I (HPI). Although sigmaS synthesis was induced and HPI activity reached the maximal level in the stationary phase, the mutant in the stationary phase showed the same susceptibility to H2O2 as the wild-type strain in the stationary phase. In addition, HPII activity, which is known to be controlled by sigmaS in Escherichia coli, was not detectable in V. vulnificus strains under the conditions tested. The mutant in the exponential phase complemented with multiple copies of either the rpoS or katG gene of V. vulnificus recovered both resistance to H2O2 and HPI activity compared with the control strain. Expression of the katG gene encoding HPI in V. vulnificus was monitored by using a katG::luxAB transcriptional fusion. The expression of this gene was significantly reduced by deletion of sigmaS in both the early exponential and late stationary phases. Thus, sigmaS is necessary for increased synthesis and activity of HPI, and sigmaS is required for exponentially growing V. vulnificus to develop the ability to survive in the presence of H2O2.