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Background: Although genetic factors are known to play a role in the pathogenesis of bladder cancer, population-level familial risk estimates are scarce. We aimed to quantify the familial risk of bladder cancer and analyze interactions between family history and smoking or alcohol consumption., Methods: Using the National Health Insurance database, we constructed a cohort of 5,524,403 study subjects with first-degree relatives (FDRs) and their lifestyle risk factors from 2002 to 2019. Familial risk was calculated using hazard ratios (HRs) with 95% confidence intervals (CIs) that compare the risk of individuals with and without affected FDRs. Interactions between family history and smoking or alcohol intake were assessed on an additive scale using the relative excess risk due to interaction (RERI)., Results: Offspring with an affected parent had a 2.09-fold (95% CI: 1.41 - 3.08) increased risk of disease compared to those with unaffected parents. Familial risks of those with affected father and mother were 2.26 (95% CI: 1.51 - 3.39) and 1.10 (95% CI: 0.27 - 4.41), respectively. When adjusted for lifestyle factors, HR reduced slightly to 2.04 (95% CI: 1.38 - 3.01), suggesting that a genetic predisposition is the main driver in the familial aggregation. Smokers with a positive family history had a markedly increased risk of disease (HR: 3.60, 95% CI: 2.27 - 5.71), which exceeded the sum of their individual risks, with statistically significant interaction (RERI: 0.72, 95% CI: 0.31 - 1.13). For alcohol consumption, drinkers with a positive family history also had an increased risk of disease, although the interaction was not statistically significant (RERI: 0.05, 95% CI: -3.39 - 3.48)., Conclusion: Smokers and alcohol consumers with a positive family history of bladder cancer should be considered a high-risk group and be advised to undergo genetic counseling., Competing Interests: None to declare., (Copyright 2023, Kim et al.)

Objective: Population-based studies of the familial aggregation of gout are scarce, and gene/environment interactions are not well studied. This study was undertaken to evaluate the familial aggregation of gout as well as assess interactions between family history and obesity or alcohol consumption on the development of gout., Methods: Using the Korean National Health Insurance database, which includes information regarding familial relationships and risk factor data, we identified 5,524,403 individuals from 2002 to 2018. Familial risk was calculated using hazard ratios (HRs) with 95% confidence intervals (95% CIs) to compare the risk in individuals with and those without affected first-degree relatives. Interactions between family history and obesity/alcohol consumption were assessed on an additive scale using the relative excess risk due to interaction (RERI)., Results: Individuals with a gout-affected first-degree relative had a 2.42-fold (95% CI 2.39, 2.46) increased risk of disease compared to those with unaffected first-degree relatives. Having both a family history of gout and being either overweight or having moderate alcohol consumption was associated with a markedly increased risk of disease, with HRs of 4.39 (95% CI 4.29, 4.49) and 2.28 (95% CI 2.22, 2.35), respectively, which exceeded the sum of their individual risks but was only statistically significant in overweight individuals (RERI 0.96 [95% CI 0.85, 1.06]). Obese individuals (RERI 1.88 [95% CI 1.61, 2.16]) and heavy drinkers (RERI 0.36 [95% CI 0.20, 0.52]) had a more prominent interaction compared to overweight individuals and moderate drinkers, suggesting a dose-response interaction pattern., Conclusion: Our findings indicate the possibility of an interaction between gout-associated genetic factors and obesity/alcohol consumption., (© 2023 American College of Rheumatology.)

Objectives: We evaluated the familial risk of seropositive rheumatoid arthritis (RA) and examined interactions between family history and smoking., Methods: Using the National Health Insurance and Health Screening Program databases, which include information on familial relationships and lifestyle factors, we identified 5 524 403 individuals with first-degree relatives (FDRs) from 2002-2018. We calculated familial risk using hazard ratios (HRs) with 95% CIs which compare the risk of individuals with and without affected FDRs. Interactions between smoking and family history were assessed on an additive scale using the relative excess risk due to interaction (RERI)., Results: Individuals with affected FDR had 4.52-fold (95% CI 3.98, 5.12) increased risk of disease compared with those with unaffected FDR. Familial risk adjusted for lifestyle factors decreased slightly (HR 4.49), suggesting that a genetic contribution is the predominant driver in the familial aggregation of RA. Smoking was associated with an increased risk of disease that was more pronounced among heavy (HR 1.92 95% CI 1.70, 2.18) compared with moderate (HR 1.15 95% CI 1.04, 1.28) smoking. In the interaction analysis, the risk associated with the combined effect of smoking and family history was higher than the sum of their individual effects, though statistically non-significant (RERI 1.30 95% CI ‒0.92, 3.51). Heavy smokers with a positive family history showed a prominent interaction (RERI 4.13 95% CI ‒0.88, 9.13) which exceeded moderate smokers (RERI 0.61 95% CI ‒1.90, 3.13), suggesting a dose-response interaction pattern., Conclusion: Our findings indicate the possibility of an interaction between RA-associated genes and smoking., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Context: Population-based studies on the familial aggregation of Graves disease (GD) are scarce and gene-environment interactions are not well-studied., Objective: We evaluated the familial aggregation of GD and assessed interactions between family history and smoking., Methods: Using the National Health Insurance database, which includes information on familial relationships and lifestyle risk factors, we identified 5 524 403 individuals with first-degree relatives (FDRs). Familial risk was calculated using hazard ratios (HRs), comparing the risk of individuals with and without affected FDRs. Interactions between smoking and family history were assessed on an additive scale using relative excess risk due to interaction (RERI)., Results: The HR among individuals with affected FDRs was 3.39 (95% CI, 3.30-3.48) compared with those without affected FDR, and among individuals with affected twin, brother, sister, father, and mother, the HRs were 36.53 (23.85-53.54), 5.26 (4.89-5.66), 4.12 (3.88-4.38), 3.34 (3.16-3.54), and 2.63 (2.53-2.74), respectively. Individuals with both a positive family history and smoking had an increased risk of disease (HR 4.68) with statistically significant interaction (RERI 0.94; 95% CI, 0.74-1.19). Heavy smokers with a positive family history showed a nearly 6-fold increased risk, which was higher than moderate smoking, suggesting a dose-response interaction pattern. Current smoking also showed a statistically significant interaction with family history (RERI 0.52; 95% CI, 0.22-0.82), while this was not observed for former smoking., Conclusion: A gene-environment interaction can be suggested between smoking and GD-associated genetic factors, which diminishes after smoking cessation. Smokers with a positive family history should be considered a high-risk group and smoking cessation should be advised., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: We quantified the familial risk of renal cell cancer (RCC) among first-degree relatives (FDRs) on a population level, and examined interactions between family history and body mass index or blood glucose., Materials and Methods: Using the National Health Insurance database, which covers the entire Korean population, and the National Health Screening Program, we constructed a cohort of 5,524,403 individuals with blood-related FDRs and their lifestyle factors from 2002 to 2018. We calculated familial risk using incidence risk ratios (IRRs) with 95% confidence intervals, which compares the risk of individuals with and without FDR. The combined effect and interaction of a given risk factor and family history of RCC were measured by the relative excess risk due to interaction., Results: Individuals with affected FDRs showed a 2.29-fold (95% CI 1.68-3.13) increased risk of disease. Familial risk adjusted for lifestyle factors showed minimal attenuation (IRR 2.25; 95% CI: 1.65-3.08), suggesting that genetic predisposition is the main contributor in the familial aggregation of RCC. Individuals with both a positive family history and overweight/obesity (IRR 3.71, 95% CI 2.50-4.92) or hyperglycemia (IRR 4.52, 95% CI 2.59-6.45) had a significantly higher risk that exceeded the sum of their individual risks, suggesting an interaction that was statistically significant (relative excess risk due to interaction 95% CI: 0.91, -0.21-2.12; 2.21, 0.28-4.14)., Conclusions: Our findings suggest an interaction between genetic and environmental factors, namely obesity and hyperglycemia. Individuals with both factors should be considered a high-risk group and advised to undergo genetic counseling.

Objective: To quantify familial risk of endometriosis among full siblings and examine interactions between family history and smoking, age at menarche or body mass index (BMI)., Design, Setting and Population: Population-based nationwide cohort study., Methods: Using data from the Korean National Health Insurance and Screening Programme databases on kinship, healthcare utilisation, lifestyle and anthropometrics, we identified 2 109 288 women with full siblings and their environmental risk factors from 2002 to 2018. Familial risks were estimated using Cox proportional-hazards models, represented as incidence risk ratios (IRR) with 95% CI. Interaction between family history and smoking, age at menarche or BMI were assessed on an additive scale., Main Outcome Measures: IRR of endometriosis among women with and without affected siblings., Results: From 19 195 women with affected siblings, 1126 developed endometriosis with an incidence of 35.45/10 000 person-years. Familial risk of endometriosis with versus without affected siblings was increased to IRR 2.75 (95% CI 2.25-3.36), and the highest risk was with affected twins (IRR 6.98; 95% CI 4.19-11.62). Women with both a family history and either smoking, early menarche or low BMI had a significantly higher risk of endometriosis compared with the general population and can be regarded as a high-risk group, the IRRs were 4.28 (95% CI 2.43-7.55), 3.47 (95% CI 2.82-4.26) and 3.09 (95% CI 2.68-3.56), respectively. Substantial effect modification of the associations was noted by smoking and early menarche, as their combined risk with family history exceeded the sum of their individual risks, which was also statistically significant., Conclusion: Genetic factors are the primary contributor to the familial aggregation of endometriosis. Significant gene-environment interaction exists between family history and smoking or early menarche., Tweetable Abstract: Significant gene-environment interaction exists between family history of endometriosis and smoking or early menarche., (© 2021 John Wiley & Sons Ltd.)

Background: Genetic and behavioral risk factors have been suggested to play a role in anterior cruciate ligament (ACL) injury. However, population-based familial risk estimates are unavailable., Purpose: To quantify familial risk of ACL injury among first-degree relatives (FDRs) after controlling for certain behavioral risk factors. To estimate the combined effect of family history and body mass index (BMI) or physical activity on the risk of ACL injury., Study Design: Cohort study; Level of evidence, 3., Methods: Using nationwide data from the Korean National Health Insurance and National Health Screening Program databases on kinship, lifestyle habits, and anthropometrics, 5,184,603 individuals with blood-related FDRs were identified from 2002 to 2018. Familial risk of ACL injury, as represented as incidence risk ratios (IRRs) with 95% CIs, was analyzed using Cox proportional hazards models among individuals with versus without affected FDRs. Analyses were adjusted for age, sex, and behavioral risk factors. Interaction testing between familial history and BMI or physical activity was performed on an additive scale., Results: The risk of ACL injury was 1.79-fold higher (IRR, 1.79; 95% CI, 1.73-1.85) among individuals with versus without affected FDRs, and the incidence was 12.61 per 10,000 person-years. The IRR (95% CI) was highest with affected twins at 4.49 (3.01-6.69), followed by siblings at 2.31 (2.19-2.44), the father at 1.58 (1.49-1.68), and the mother at 1.52 (1.44-1.61). High BMI and high level of physical activity were significantly associated with the risk of ACL injury. Individuals with positive family history and either high BMI or physical activity had a 2.59- and 2.45-fold increased risk of injury as compared with the general population, respectively, and the combined risks exceeded the sum of their independent risks., Conclusion: Familial factors are risk factors for ACL injury with an additional contribution of 2 behavioral factors: BMI and physical activity level. A significant interaction was observed between family history of ACL injury and high BMI/level of physical activity.

Background & Aims: Despite the rapid increase in inflammatory bowel disease (IBD), population-level familial risk estimates of IBDs still are lacking in Asian-Pacific countries. We aimed to quantify the familial risk of incident IBD among first-degree relatives (FDRs) of individuals with IBD according to age, sex, and familial relationship., Methods: Using the South Korea National Health Insurance database (2002-2017), which has complete population coverage and confirmed accuracy of both FDR information and IBD diagnoses, we constructed a cohort of 21,940,795 study subjects comprising 12 million distinct families. We calculated incidence risk ratios of ulcerative colitis (UC) or Crohn's disease (CD) in individuals of affected FDRs compared with individuals without affected FDRs., Results: Of 45,717 individuals with UC and 17,848 individuals with CD, 3.8% and 3.1% represented familial cases, respectively. Overall, there was a 10.2-fold (95% CI, 9.39-11.1) and a 22.1-fold (95% CI, 20.5-24.5) significantly higher adjusted risk of UC and CD among FDRs of individuals with vs without IBD. Familial risk was highest among twins, followed by nontwin siblings, and then offspring of affected parents. Familial risk generally was higher within generations (sibling-sibling) vs between generations (parent-offspring). Familial risk also increased with the increasing number of affected FDRs., Conclusions: According to this population-based analysis, there is a substantially increased risk of IBD among FDRs of affected individuals, with the highest risk among siblings and for CD. These findings might help with an earlier diagnosis and appropriate therapeutic intervention in FDRs of individuals with IBD. Dedicated studies are needed to evaluate the contributions of shared early-in-life environmental exposures and genetic factors., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Few small-scale studies have reported a genetic and familial predisposition in Hashimoto's thyroiditis (HT), however, quantified familial risk estimates from population-level data are unavailable. We aimed to estimate the incidence and familial risk of HT among first-degree relatives (FDR) according to age, sex, and family relationships. Methods: We conducted a population-based study in the general population of Korea from 2002 to 2017. Using the nationwide health insurance database, which has full population coverage and family relationship information, a cohort of 22 million individuals with blood-related FDR comprising 12 million families were followed up for a familial occurrence of HT. Age- and sex-adjusted incidence risk ratios (IRRs) were calculated in individuals with an affected FDR compared with those without an affected FDR. Results: Among 21,940,795 individuals, 234,912 had an HT-affected FDR, of whom 2425 familial cases developed HT with an incidence of 7.12/10,000 person-years. The familial risk for HT was 6.5-fold (95% confidence interval [CI]: 6.24-6.78) higher in individuals with versus without affected FDR. According to relationship, familial risks were IRR 102.71, IRR 7.80, IRR 5.54, and IRR 5.52 with an affected twin, sibling, mother, and father, respectively, and the corresponding incidence (/10,000 person-years) was 115.57, 10.66, 5.73, and 5.91. Same-sex twins had three times higher risk of developing HT than opposite-sex twins (IRR 121.01 vs. 21.46). The sex-specific familial risk was higher in males than females. The risks demonstrated age dependence, being higher in younger age groups. Conclusions: This study represents the largest population-based study of familial HT risk in Asia. We demonstrated elevated familial risk of incident HT among FDR, but with lower magnitude as those observed in previous studies. Familial risk increased with the degree of genetic relatedness among FDR indicating a prominent role of genetic factors in the familial aggregation of HT. Elevated risks in the younger age groups should motivate clinicians to screen people with a family history, especially those <30 years.

Objective: Previous studies have indicated that Behçet's disease (BD) has a genetic component, however population-level familial risk estimates are unavailable. We quantified the familial incidence and risk of BD in first-degree relatives (FDR) according to age, sex and type of family relationship., Methods: Using the Korean National Health Insurance database, which has full population coverage and confirmed FDR information, we constructed a cohort of 21 940 795 individuals comprising 12 million families, which were followed for a familial occurrence of BD from 2002 to 2017. Age- and sex-adjusted incidence risk ratios for BD were calculated in individuals with affected FDR compared with those without affected FDR., Results: Among the total study population, 53 687 individuals had affected FDR, of whom 284 familial cases developed BD with an incidence of 3.57/104 person-years. The familial risk (incidence) for BD was increased to 13.1-fold (2.71/104 person-years) in individuals with an affected father, 13.9-fold (3.11/104 person-years) with affected mother, 15.2-fold (4.9/104 person-years) with an affected sibling and the highest risk was 165-fold (46/104 person-years) with an affected twin. Familial risks showed age dependence, being higher in younger age groups. The sex-specific familial risk was similar in males and females., Conclusion: This study provides quantified estimates of familial incidence and risk in FDR of BD patients in an entire population. Familial risks were higher within generation (sibling-sibling) vs between generations (parent-offspring). This implicates complex interactions between genetic factors and shared childhood environmental exposures in the pathogenesis of BD., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Few nationally representative studies have evaluated the epidemiology of PA (pituitary adenoma). This South Korean study evaluated the incidence of different PA subtypes, cardiovascular disease (CVD), and related mortality., Methods: This population-based study evaluated 31,898 patients with PA during 2005-2015. The incidence of PA, mortality, and CVD occurrence in PA cases were evaluated during a median follow-up of 5.3 years (range: 0-10 years). Cox regression analysis was used to evaluate the associations between CVD and mortality., Results: The annual incidences (per 100,000 population) were 3.5 for non-functioning pituitary adenoma (NFPA), 1.6 for prolactinoma (PRL), 0.5 for growth hormone-secreting pituitary adenoma (GH), and 0.2 for adrenocorticotropic or thyroid-stimulating hormone-secreting pituitary adenoma (ACTH + TSH). The standardized mortality ratios were 1.9 for ACTH + TSH, 1.7 for NFPA with hypopituitarism, 1.4 for NFPA without hypopituitarism, 1.3 for GH, and 1.1 for PRL. During 2005-2015, the overall incidence of CVD among PA patients was 6.6% (2106 cases), and the standardized incidence ratios were 4.1 for hemorrhagic stroke, 3.0 for ischemic stroke, and 1.7 for acute myocardial infarction. The standardized incidence ratios for stroke were significantly higher in the ACTH + TSH and NFPA groups, which also had higher risks of CVD-related mortality, relative to the PRL and GH groups., Conclusion: South Korea had a relatively high incidence of NFPA. The incidence of stroke was highest for ACTH + TSH and NFPA, which was directly related to mortality during long-term follow-up. Patients with these types of PA should receive stroke prevention measures to reduce their risk of mortality.

Background and Purpose: Genetic factors have been known to play a role in the etiology of moyamoya disease (MMD); however, population-level studies quantifying familial risk estimates are unavailable. We aimed to quantify familial incidence and risk for MMD in first-degree relatives (FDR) in the general population of Korea., Methods: By using the Korean National Health Insurance database which has complete population coverage and confirmed FDR information, we constructed a cohort of 21 940 795 study subjects constituting 12 million families with blood-related FDR and followed them for a familial occurrence of MMD from 2002 to 2017. Incidence risk ratios were calculated as MMD incidence in individuals with affected FDR compared with those without affected FDR, according to age, sex, and family relationships., Results: Among total study subjects, there were 22 459 individuals with affected FDR, of whom 712 familial cases developed MMD with an incidence of 21.8/10 4 person-years. Overall, the familial risk for MMD was 132-fold higher in individuals with versus without affected FDR. Familial risk (incidence risk ratio; incidence/10 4 person-years) increased with the degree of genetic relatedness, being highest in individuals with an affected twin (1254.1; 230.0), followed by a sibling (212.4; 35.6), then mother (87.7; 14.4) and father (62.5; 10.4). Remarkably, there was no disease concordance between spouses. The risks were age-dependent and were particularly high in younger age groups. Familial risks were similar in males and females, and the risk of disease transmission was higher in same-sex parent-offspring and sibling pairs., Conclusions: Our study indicates that genetic predisposition is the predominant driver in MMD pathogenesis, with minimal contribution of environmental factors. These results could be utilized to direct future genetic studies and clinical risk counseling.

Purpose: To evaluate the incidence, visual prognosis, and mortality in retinopathy of prematurity (ROP) in Korea., Methods: We used the National Health Insurance and the Korean Disability Registry database, which covers the entire newborn population in 2006 to 2014 and includes information on all newborns diagnosed with ROP until 2016. Using these databases, we evaluated the incidence, rate of visual impairment (VI), and mortality in patients with ROP according to the birth weight categories and treatment modalities., Results: The ROP incidence per 1000 newborns was 1.99, which broke down into 317.14 in the very low birth weight (VLBW) less than 1500 g population, 25.45 in the 1500 to 2499 g population, and 0.29 in the 2500 g or greater population. When assessed at age 10, the VI rate was 2.2 per 100 person-years, which was highest at 4.5 per 100 person-years in the VLBW population compared with the population in other birth weight categories. Among treated cases, the proportion of VI in patients undergoing laser photocoagulation or cryotherapy was 1.6% (42/2595), which was lower than the 2.9% (2/68) of patients treated with anti-vascular endothelial growth factor injection, and 32.2% (82/255) of patients undergoing vitrectomy or scleral buckling. The mortality rate was 4.8 per 1000 person-years, which was highest in the VLBW population, but similar across treatment modalities., Conclusions: The ROP incidence in Korea was approximately 1 in 500 among all newborns, and 1 in 3 in the VLBW population. As the first nationwide population-based study of long-term visual prognosis in ROP, we report the higher VI rate in ROP than previously determined in other studies. Differences in visual outcomes and comparable mortality risks between treatment modalities require further verification.

Pilocarpine-induced rat epilepsy model is an established animal model that mimics medial temporal lobe epilepsy in humans. The purpose of this study was to investigate neuroimaging abnormalities in various stages of epileptogenesis and to correlate them with seizure severity in pilocarpine-induced rat epilepsy model. Fifty male Sprague-Dawley rats were subject to continuous video and electroencephalographic monitoring after inducing status epilepticus (SE) and seizure severity was estimated by frequency and total durations of class 3 to 5 spontaneous recurrent seizures (SRS) by modified Racine's classification. The 7.0 Tesla magnetic resonance imaging (MRI) with high resolution flurodeoxyglucose positron emission tomography (FDG-PET) was performed at 3 hours, 1, 3, 7 days and 4 weeks after the initial insult. The initial SRS was observed 9.7±1.3 days after the pilocarpine injection. MRI revealed an abnormal T2 signal change with swelling in both hippocampi and amygdala in acute (day 1 after injection) and latent phases (days 3 and 7), in association with PET hypometabolism in these areas. Interestingly, the mean frequency of class 3 to 5 SRS was positively correlated with abnormal T2 signals in hippocampal area at 3 days. SRS duration became longer with more decreased glucose metabolism in both hippocampi and amygdala at 7 days after pilocarpine injection. This study indicates that development and severity of SRS at chronic phase could be closely related with structural and functional changes in hippocampus during the latent period, a pre-epileptic stage.

Objectives: The objective of this study was to investigate the epidemiological features of primary Sjögren's syndrome (pSS) in Korea at a national level, including the incidence, mortality, and causes of death., Methods: We used a national, population-based registry database called the Rare Intractable Disease Registration Program from the Health Insurance Review and Assessment Service to obtain pSS patient data for the period between 2010 and 2014. pSS was diagnosed by a physician based on uniform criteria. We also used data from Statistics Korea to confirm the mortality and causes of death., Results: Between 2010 and 2014, the total number of patients newly diagnosed with pSS was 5891, resulting in an annual incidence of 2.34 per 100,000 individuals. The female-to-male ratio was 14.5:1. A total of 114 pSS patients died during the study period. The overall survival rate of pSS patients was 99.0%, and the 1-year, 2-year, and 5-year survival rates were 98.7%, 98.1%, and 97.1%, respectively, and the standardized mortality ratio (SMR) was 1.47 (2.14 for males and 1.35 for females). The most common causes of death were respiratory disease (n = 25; 21.9%) followed by circulatory diseases (n = 21; 18.4%), musculoskeletal connective tissue diseases (n = 21; 18.4%), and cancer (n=19; 16.7%)., Conclusions: The national incidence of pSS in Korea presented in this study was lower in comparison with reports from other countries. However, the mortality rate was significantly higher than the corresponding values in the age- and gender-matched general population. The higher mortality in pSS patients is attributable to respiratory diseases and lung cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Studies investigating the epidemiology and mortality of Takayasu Arteritis (TA) are scarce. The objective of this study was to provide information regarding the epidemiology of TA, such as the incidence, prevalence, survival and cause of death in Korea., Methods: We used a national, population-based database maintained by the Rare Intractable Disease registration program and the Health Insurance Review and Assessment Service, which includes information on all TA patients, diagnosed based on uniform criteria. We also used data from Statistics Korea linked with RID database to confirm survival and cause of death. We analyzed data for the period 2008-2012., Results: During study period, there were 612 new patients with TA, with a female-to-male ratio of 4.3:1. The annual mean incidence was 0.24 per 10 5 people, and the prevalence was 2.82 per 10 5 people in 2012. The average annual mortality rate was 0.02 per 10 5 people, and the standardized mortality ratio was 3.1. The overall survival of patients with TA was 96.6%, which was significantly lower than that in the general population. Cardiovascular disease was the most common cause of death, accounting for 29 of the 64 deaths (45.3%), followed by neoplasms in 9 patients (14.1%)., Conclusions: The incidence and prevalence presented in this study are the highest ever reported. The survival of patients with TA was significantly lower than that of the general population, and the main cause of death was cardiovascular disease. This study reflects the need for greater awareness of TA, especially in Asian countries., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To determine the prevalence and mortality of retinitis pigmentosa (RP) patients in Korea., Design: Population-based retrospective cohort study., Methods: We used data covering the 2011-2014 period from the Rare Intractable Disease (RID) registry and Health Insurance Review and Assessment (HIRA) service, which include information on all patients diagnosed with RP based on predefined diagnostic criteria. Using the HIRA-RID database, we evaluated the prevalence and age at diagnosis of RP patients across the entire Korean population. We further linked the data from Statistics Korea to the HIRA-RID database to confirm mortality and causes of death., Results: The prevalence in the total population across all ages was 11.09 per 10 5 people, and the prevalence in those over the age of 40 was 16.16 per 10 5 people. The age at diagnosis ranged from 0 to 95 and, on average, was 44.8. The standardized mortality ratio (SMR) was 1.56 for all ages, peaking at 2.61 in men aged 40-59, which was attributed to 6.6-fold higher suicide rates than the same age group in the general male population., Conclusions: This is the first nationwide epidemiologic study of RP patients covering the entire population of all ages. The results suggest that the prevalence of RP in Korea is about 1 in 9000 for all ages and 1 in 6000 for those over 40 years of age. The higher mortality of RP patients than that of the general population is attributable to a high suicide rate in male RP patients of working ages, which necessitates a careful attention to their mental health., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Technique failure is an important issue for peritoneal dialysis (PD) patients. In this study, we aimed to analyze technique failure rate in detail and to determine the predictors for technique failure in Korea., Methods: We identified all patients who had started dialysis between January 1, 2005, and December 31, 2008, in Korea, using the Korean Health Insurance Review and Assessment Service database. A total of 7,614 PD patients were included, and the median follow-up was 24.9 months., Results: The crude incidence rates of technique failure in PD patients were 54.1 per 1,000 patient-years. The cumulative 1-, 2-, and 3-year technique failure rates of PD patients were 4.9%, 10.3%, and 15.6%, respectively. However, those technique failure rates by Kaplan-Meier analysis were overestimated compared with the values by competing risks analysis, and the differences increased with the follow-up period. In multivariate analyses, diabetes mellitus and Medical Aid as a crude reflection of low socioeconomic status were independent risk factors in both the Cox proportional hazard model and Fine and Gray subdistribution model. In addition, cancer was independently associated with a lower risk of technique failure in the Fine and Gray model., Conclusion: Technique failure was a major concern in patients initiating PD in Korea, especially in diabetic patients and Medical Aid beneficiaries. The results of our study offer a basis for risk stratification for technique failure.

Background: Dialysis patients are at high risk for cardiovascular diseases, but until now there have been no detailed analyses of the incidences among Asian patients initiating dialysis. The aims of this study were to determine the incidence rates of major adverse cardiac and cerebrovascular events (MACCE) and to compare them between incident HD patients and PD patients., Methods: We included all patients who had started dialysis between January 1, 2005 and December 31, 2008 in Korea, and analyzed 30,279 eligible patients [22,892 hemodialysis (HD) patients and 7387 peritoneal dialysis (PD) patients] by intention-to-treat. Median follow-up was 21.5 months., Results: The crude incidence rates were as follows: MACCE, 182 per 1000 patient-years (PY); major adverse cardiac events (MACE), 138/1000 PY; all-cause mortality, 116/1000 PY; non-fatal acute myocardial infarction (AMI), 18/1000 PY; target vessel revascularization (TVR), 17/1000 PY; and non-fatal stroke, 60/1000 PY. When comparing all baseline covariate-adjusted relative risks between HD and PD patients, HD is overall superior to PD in terms of MACCE. Further examined by each endpoint, all-cause mortality, non-fatal AMI, and TVR occurred significantly more frequently in patients on PD than in those on HD, whereas non-fatal hemorrhagic stroke occurred significantly more frequently in patients on HD than in those on PD., Conclusions: The incidence of MACCE may be different from Western dialysis patients. HD is overall superior to PD in terms of MACCE as an initial dialysis modality. Underlying mechanisms differentially affecting cardiovascular outcomes by dialysis modality remain to be further elucidated., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The aim of this study was to investigate whether the survival rate among Korean dialysis patients changed during the period between 2005 and 2008 in Korea., Materials and Methods: A total of 32357 patients who began dialysis between January 1, 2005 and December 31, 2008 were eligible for analysis. Baseline demographics, comorbidities, and mortality data were obtained from the database of the Health Insurance Review & Assessment Service., Results: Kaplan-Meier curves according to the year of dialysis initiation showed that the survival rate was significantly different (log-rank test, p=0.005), most notably among peritoneal dialysis (PD) patients (p<0.001), although not among hemodialysis (HD) patients (p=0.497). In multivariate analysis, however, patients initiating either HD or PD in 2008 also had a significantly lower risk of mortality compared to those who began dialysis in 2005. Subgroup survival analysis among patients initiating dialysis in 2008 revealed that the survival rate of PD patients was significantly higher than that of HD patients (p=0.001), and the survival benefit of PD over HD remained in non-diabetic patients aged less than 65 years after adjustment of covariates., Conclusion: Survival of Korean patients initiating dialysis from 2005 to 2008 has improved over time, particularly in PD patients. In addition, survival rates among patients initiating dialysis in 2008 were different according to patients' age and diabetes, thus we need to consider these factors when dialysis modality should be chosen.

Background: Although a rising trend in the incidence of inflammatory bowel disease (IBD) in Asia has been recognized, national-level, population-based studies are lacking. In this study, we investigate the epidemiological features and natural course of IBD in Korea, including incidence, bowel resection rates, survival, and cause of death., Methods: We analyzed the Rare Intractable Disease registration and Health Insurance Review and Assessment Services claims database, which include information on every patients with IBD diagnosed through uniform criteria from 2006 to 2012. Twenty-seven thousand four hundred nineteen patients with IBD newly diagnosed from 2006 to 2012 were traced to bowel resection, survival, and cause of death., Results: During study period, mean annual incidence for ulcerative colitis was 4.6 per 10 and for Crohn's disease (CD) was 3.2 per 10. Bowel resection rates at 1 and 5 years for patients with ulcerative colitis were 0.8% and 2.1%, respectively, and for patients with CD were 5.0% and 9.1%, respectively. Survival of patients with CD was lower than that of the general population, whereas patients with ulcerative colitis had similar survival. In patients with CD, mortality for colon cancer, lung cancer, and gastrointestinal disease was significantly increased compared with general population., Conclusions: Incidence of IBD found in our study is the highest in East Asia. Lower bowel resection rates and higher survival compared to those of Western nations suggest that the natural course of IBD may be different between East Asia and the West.

To date, only a few large-scale studies have measured the effect of dialysis modality on mortality in Asian populations. Here, we sought to compare survival between incident hemodialysis (HD) and peritoneal dialysis (PD) patients using the Korean Health Insurance Review & Assessment Service database. This enabled us to perform a population-based complete survey that included 32,280 incident dialysis patients and followed them for a median of 26.5 months. To reduce biases due to nonrandomization, we first matched 7049 patient pairs with similar propensity scores. Using the log-rank test, we found the mortality rate in PD patients was significantly higher than that in HD patients. Subsequent subgroup analyses indicated that in older patients (55 years and older), with the exception of the subgroup of patients with no comorbidities and the subgroup of patients with malignancy, PD was consistently associated with a higher mortality rate. In younger patients (under 55 years), regardless of the covariates, the survival rate of PD patients was comparable to that of HD patients. Thus, while the overall mortality rate was higher in incident PD patients, mortality rates of some incident PD and HD patients were comparable in Korea.

Background and Purpose: There is a scarcity of information on the epidemiology and natural course of moyamoya disease. The aim of this study was to investigate the nationwide epidemiological features of moyamoya disease in Korea, including incidence, prevalence, and survival., Methods: We used the data from nationwide, population-based Health Insurance Review and Assessment Service claims database and Rare Intractable Disease registration program, which includes physician-certified diagnoses based on uniform criteria for moyamoya disease from 2007 to 2011. Age-specific incidence and prevalence were calculated, and survival was examined using Kaplan-Meier method., Results: The total number of patients with moyamoya disease was 8154 in 2011, with a female-to-male ratio of 1.8. The incidence from 2007 to 2011 was 1.7 to 2.3/10(5), and the prevalence in 2011 was 16.1/10(5). In total, 66.3% of patients aged 0 to 14 years underwent surgery, whereas only 21.5% in the older than 15 years age group underwent surgery. The 1- and 5-year survival rates of adult patients were 96.9% and 92.9%, respectively, and of child patients were 99.6% and 99.3%, respectively., Conclusions: The prevalence and incidence presented in this study are higher than those in previous studies. This study demonstrates that the burden of moyamoya disease in Korea is substantial.

Background: Although the proportion of the elderly patients with incident end-stage renal disease (ESRD) patients has been increasing in Korea, there has been a lack of information on outcomes of dialysis treatment. This study aimed to assess the survival rate and to elucidate predictors for all-cause mortality among elderly Korean patients initiating dialysis., Methods: We analyzed 11,301 patients (6,138 men) aged 65 years or older who had initiated dialysis from 2005 to 2008 and had followed up (median, 37.8 months; range, 3-84 months). Baseline demographics, comorbidities and mortality data were obtained using the database from the Health Insurance Review & Assessment Service., Results: The unadjusted 5-year survival rate was 37.6% for all elderly dialysis patients, and the rate decreased with increasing age categories; 45.9% (65∼69), 37.5% (70∼74), 28.4% (75∼79), 24.1% (80∼84), and 13.7% (≥85 years). The multivariate Cox proportional hazard model revealed that age, sex, dialysis modality, the type of insurance, and comorbidities such as diabetes mellitus, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, hemiparesis, liver disease, and any malignancy were independent predictors for mortality. In addition, survival rate was significantly higher in patients on hemodialysis compared to patients on peritoneal dialysis during the whole follow-up period in the intention-to-treat analysis., Conclusions: Survival rate was significantly associated with age, sex, and various comorbidities in Korean elderly patients initiating dialysis. The results of our study can help to provide relevant guidance on the individualization strategy in elderly ESRD patients requiring dialysis.

Ischemic-reperfusion injury is thought to be a cause of idiopathic carpal tunnel syndrome (CTS). The purpose of this study was to determine whether oxidative stress caused by ischemia-reperfusion injury in subsynovial connective tissue is associated with idiopathic CTS and its symptoms. Bioptic samples of tenosynovial tissue were collected from 20 idiopathic CTS patients during surgery. Control specimens of tenosynovial tissue were collected from eight non-CTS patients. Analysis included histological and immunohistochemical examination for the distribution of endothelial nitric oxide synthase (eNOS), nuclear factor (NF)-κβ, and transforming growth factor (TGF)-β RI in subsynovial connective tissues. Histological examinations showed a marked increase in fibroblast density and vascular proliferation in specimens from CTS patients. The expressions of eNOS, NF-κβ, and TGF-β RI in fibroblasts and vascular endothelial cells of subsynovial connective tissues of patients were significantly higher than in those of controls. A significant positive correlation was found between the subjective symptom severity of CTS, and the immunoreactivities of eNOS and NF-κβ. This study suggests that oxidative stress in subsynovial connective tissue is related to CTS and its symptoms., (© 2010 Orthopaedic Research Society.)

The purpose of this study was to investigate estrogen receptor (ER) expression in tenosynovial tissues of postmenopausal woman with idiopathic carpal tunnel syndrome (CTS) to determine whether estrogen contributes to the pathogenesis of this condition. Biopsy samples of tenosynovial tissues were collected from 14 postmenopausal women (mean age; 57, range; 46-69 years) undergoing surgery for idiopathic CTS, and control specimens of tenosynovial tissue were collected from 6 postmenopausal women (mean age; 59, range; 48-68 years) without CTS. Histological and immunohistochemical examinations were performed to determine the distributions of ER-α and ER-β in tenosynovial tissues. Histological examinations showed a significant increase in fibroblast cell densities in the specimens from the carpal tunnel syndrome patients. ER-α and ER-β immunoreactivities were observed in fibroblasts and in the synovial lining cells of tenosynovial tissues, and these were significantly greater in patients than in controls. This study suggests that the up-regulations of ERs in the tenosynovial tissue are associated with idiopathic CTS in postmenopausal women., (© 2010 Orthopaedic Research Society.)

Syndecan-2, a transmembrane heparan sulfate proteoglycan, is a critical mediator in the tumorigenesis of colon carcinoma cells. We explored the function of syndecan-2 in melanoma, one of the most invasive types of cancers, and found that the expression of this protein was elevated in tissue samples from both nevus and malignant human melanomas but not in melanocytes of the normal human skin tissues. Similarly, elevated syndecan-2 expression was observed in various melanoma cell lines. Overexpression of syndecan-2 enhanced migration and invasion of melanoma cells, whereas the opposite was observed when syndecan-2 levels were knocked down using small inhibitory RNAs. Syndecan-2 expression was enhanced by fibroblast growth factor-2, which is known to stimulate melanoma cell migration; however, alpha-melanocyte-stimulating hormone decreased syndecan-2 expression and melanoma cell migration and invasion in a melanin synthesis-independent manner. Furthermore, syndecan-2 overexpression rescued the migration defects induced by alpha-melanocyte-stimulating hormone treatment. Together, these data strongly suggest that syndecan-2 plays a crucial role in the migratory potential of melanoma cells.

6-Hydroxydopamine (6-OHDA), a neurotoxin that causes the death of dopamine (DA) neurons, is commonly used to produce experimental models of Parkinson's disease (PD) in rodents. In the rat model of PD first described by Sauer and Oertel, DA neurons progressively die over several weeks following a striatal injection of 6-OHDA. It is generally assumed that DA neurons die through apoptosis after exposure to 6-OHDA, but data supporting activation of a caspase enzymatic cascade are lacking. In this study, we sought to determine if caspases involved in the intrinsic apoptotic cascade play a role in the initial stages of 6-OHDA-induced death of DA neurons in the progressively lesioned rat model of PD. We found that injection of 6-OHDA into adult rat striatum did not activate caspase-9 or caspase-3 or increase levels of caspase-dependent cleavage products in the substantia nigra at various survival times up to 7 days after the lesion, even though this paradigm produced DA neuronal loss. These data suggest that in the adult rat brain DA neurons whose terminals are challenged with 6-OHDA do not die through a classical caspase-dependent apoptotic mechanism., ((c) 2007 Wiley-Liss, Inc.)

The purpose of this study was to compare the proportion of therapeutic interventions that is supported by scientific evidence between hospital-based and community-based primary care clinics. The study setting is a primary care clinic in university-affiliated tertiary hospital and community-based primary care clinic in a region in Seoul. A retrospective review of patients' medical records was done according to the primary diagnosis and treatment for 890 patients in community-based clinic and 307 in hospital-based clinic. The evidence for the intervention was searched for in Medline (1966-2001) and other evidence-based databases. The evidence was then classified as one of the three categories (i) evidence from randomised controlled trials (RCTs); (ii) convincing non-experimental evidence; and (iii) interventions without substantial evidence. In the hospital-based clinics, out of 356 primary diagnosis and treatment pairs, 59.6% were supported by evidence from at least one RCTs, and 19.4% were supported by convincing non-experimental evidence. In the community-based clinics, 47.1% out of 893 pairs and 10.5% fell into each category. As a result, the proportion of interventions in community settings that were based on evidence meeting our criteria was significantly lower than that of the hospital-based settings. To facilitate evidence-based practice, supportive activity should be focused on the primary care settings based on community where medical practices are less evidence-based.

Objective: It has been known that maternal oxidative stress during pregnancy plays an important role in fetal growth. However, the association between antioxidant vitamin levels and birth outcomes is not conclusive. We investigated the relationship between maternal serum levels of vitamins C and E during the second trimester and birth weight and length., Design: Prospective cohort study., Setting: Outpatient-clinic of obstetrics, Ewha Womans University Hospital, South Korea., Subjects and Methods: The study subjects were 239 healthy, pregnant women who visited an obstetric clinic for antenatal care, and their singleton live births, in Seoul, Korea, between August 2001 and March 2003. We measured the levels of vitamins C and E in maternal serum during the period 24-28 gestational weeks. Each woman was interviewed for dietary intake by trained interviewers during the second trimester., Results: The serum concentration of maternal vitamin C during the second trimester was significantly associated with birth weight and length in the group of full-term deliveries. An increase of 1 microg/ml in the serum vitamin C level increased the birth weight by 27.2 g and the birth length by 0.17 cm. When we considered the levels of vitamins C and E together in the relationship with birth weight and length, we found that the heaviest birth weight and the longest birth length belonged to the group of upper vitamin C/upper vitamin E. However, dietary intake estimated by 24-h recall method was not a predictor of the levels of serum vitamins C and E., Conclusion: We found that maternal serum vitamin C levels during the second trimester were positively correlated with birth weight and length in full-term babies. We also found that birth weight and length were highest when the levels of both vitamins C and E were high. Our results indicate the importance of antioxidant nutrient balance for pregnant women who are exposed to various oxidants through food, drinking water, or inhaled air.

The effects of continuous infusion of NMDA receptor antagonist MK-801 on the modulation of NMDA receptor subunits NR1, NR2A, NR2B, and NR2C were investigated by using in situ hybridization study. Differential assembly of NMDA receptor subunits determines their functional characteristics. Continuous intracerebroventricular (i.c.v.) infusion with MK-801 (1 pmol/10 microl/h) for 7 days resulted in significant modulations in the NR1, NR2A, and NR2B mRNA levels without producing stereotypic motor syndromes. The levels of NR1 mRNA were significantly increased (9-20%) in the cerebral cortex, striatum, septum, and CA1 of hippocampus in MK-801-infused rats. The levels of NR2A mRNA were significantly decreased (11-16%) in the CA3 and dentate gyrus of hippocampus in MK-801-infused rats. In contrast to NR2A, NR2B subunit mRNA levels were increased (10-14%) in the cerebral cortex, caudate putamen, and thalamus. However, no changes of NR2C subunits in cerebellar granule layer were observed. Using quantitative ligand autoradiography, the binding of NMDA receptor ligand [3H]MK-801 was increased (12-25%) significantly in almost all brain regions except in the thalamus and cerebellum after 7 days infusion with MK-801. These results suggest that region-specific changes of NMDA receptor subunit mRNA and [3H]MK-801 binding are involved in the MK-801-infused adult rats.

Purpose: By using both in vivo and in vitro (organ-cultured) systems, the optimal concentrations of hEGF to enhance epithelial healing after alkali wounds were evaluated in the rabbit cornea., Methods: Alkali-injured corneas (pi = 5.5 mm, 1 N NaOH, 60 s) were treated with 0.01, 0.1, 1.0, 10 and 100 ng/ml hEGF for the in vitro study. The healing of epithelium and endothelium was determined at 1, 2, 3, 4, and 6 days after treatment. For the in vivo experiment, the eyes were treated with 2, 5, 10, and 50 microg/ml hEGF 3 times per day. The measurement of epithelial healing rate, transmission electron microscopy and immunohistochemical observation were performed after 7 days treatment., Results: In in vitro tests, hEGF enhanced the epithelial healing rates, showing a maximum enhancement at the concentration of 1.0 ng/ml, and endothelial healing was increased at 100 ng/ml. In in vivo studies, no significant difference was observed in the rates of epithelial healing between control and each hEGF-treated group. Among the tested concentrations, 5 microg/ml hEGF induced the most active proliferation of basal cells and 50 microg/ml hEGF remarkably produced a vascular ingrowth to the central wound area. The thickness of re-surfaced epithelium was increased by hEGF in a concentration-dependent manner., Conclusions: The results of the present study indicate that a low concentration of hEGF may selectively enhance epithelial healing without affecting endothelial healing. The optimal concentration of hEGF for the stimulation of epithelial healing appears to be 5 microg/ml in rabbit corneal alkali wounds.

A systematic review was conducted of the literature on human resources planning (HRP) in dentistry in Canada, critically assessing the scientific strength of 1968-1999 publications. Inclusion and exclusion criteria were applied to 176 peer-reviewed publications and "grey literature" reports. Thirty papers were subsequently assessed for strength of design and relevance of evidence to objectively address HRP. Twelve papers were position statements or experts' reports not amenable for inclusion in the system. Of the remaining 18 papers, 4 were classified as projections from manpower-to-population ratios, 4 as dental practitioner opinion surveys, 8 as estimates of requisite demand to absorb current capacity and 2 as need-based, demand-weighted studies. Within the 30.5 years reviewed, 53.4% of papers were published between 1982 and 1987. Overall, many papers called for a reduction in human resources, a message that dominated HRP during the 1980s, or noted an increase in the demand for services. HRP publications often had questionable strength or analytic frameworks. The paradigm of busyness-scarcity evolved from a belief around an economic model for the profession into a fundamental tenet of HRP. A formal analysis to establish its existence beyond arbitrary dentist:population ratios has usually been lacking.

This study was undertaken to determine the prevalence of dental caries in children ages 6-14, from fluoridated and non-fluoridated areas in British Columbia, Canada, and the effects of receiving certain fluoride preventive procedures during childhood. Children from two communities were surveyed using a modified Decayed, Missing and Filled Tooth Surface Index (D1D2MFS). Questionnaires on the use of various fluoride preventive practices and residence histories during childhood were collected. Completed questionnaires were returned and exams were performed on 1131 children. Crude caries prevalence scores for the different fluoride exposure groups were tested for differences in dental age and the level of educational attainment of parents and/or guardians. No significant group differences were found. The 110 children with lifelong exposure only to fluoridated water had 35%, or 0.88 (S.D. = 2.91), fewer decayed or filled tooth surfaces per child (P < 0.07) than children with no reported exposure to systemic fluorides. For the 122 children who had taken fluoride supplements for 4 yr or more, 0.67 fewer decayed and filled tooth surfaces (26% reduction) were observed per child when compared to children with no exposure to fluoridated water or supplements. For children who used fluoride supplements for less than 4 yr, no significant benefits were observed. Approximately 75% of the caries prevalence for control and fluoride-exposed groups was on pit and fissured surfaces. Reductions by surface type showed savings on both smooth and pit and fissured surfaces.

An increase in the prevalence of dental fluorosis among children in North America is well documented. Published reports of the relationship between the occurrence of dental fluorosis and early exposure to various fluorides and the use of different types of infant feeding practices have begun to provide insights into possible causes for this increase. This study was designed to investigate this issue for children living in a non-fluoridated and a fluoridated community in British Columbia, Canada. Parents or guardians completed a questionnaire which detailed exposure to different types of fluorides and infant feeding practices during the first 6 yr of life. Completed questionnaires were returned and examinations were performed on 1131 children. 60% of children had dental fluorosis, and only 8% presented with scores of 2 or greater. Logistic regression analyses showed that the use of infant formula and parental educational attainment were significantly associated with the occurrence of dental fluorosis in the range of scores from 2 to 6. Despite these statistically significant findings, these variables actually had little additional predictive value beyond a chance occurrence in determining which children would have dental fluorosis.

Increasing prevalence of dental fluorosis for children both from fluoridated and non-fluoridated communities are now well documented. Along with recent studies purporting possible adverse health effects from fluorides, this proven public health intervention is again being challenged. This study was undertaken to determine the prevalence of dental fluorosis for children from fluoridated and non-fluoridated areas in British Columbia. In addition, children and parents were provided with an opportunity to express concerns about the aesthetics of the child's anterior teeth. Children from representative schools in two communities were surveyed using the Tooth Surface Index of Fluorosis (TSIF). Questionnaires were sent home to parents to detail their child's use of various fluoride preventive practices and residence histories. Completed questionnaires were returned and exams were performed on 1131 children. Of those examined, 60% had dental fluorosis on at least two tooth surfaces, only 8% had scores ranging from "2" to "6", and 52% were classified with a score of "1". Parental and child ratings on the aesthetics or color of the child's teeth suggests that there are few children with aesthetic problems in the TSIF category of "1". While concerns of parents were more common, the actual source of those concerns was not assessed in the questionnaire. Not unexpectedly, children with fluorosis on anterior teeth ranging between TSIF scores of "2" to "6" appear to have increased concerns about tooth color. Data from children with confirmed residence histories from fluoridated communities suggest that the occurrence of aesthetic problems in these children is rare.