Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth Syndrome.

Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the inner mitochondrial membrane. Although TAFAZZIN is ubiquitously expressed, BTHS involves a complex combination of tissue specific phenotypes including cardiomyopathy, neutropenia, skeletal myopathy, and growth delays, with a relatively minimal neurological burden. To understand both the developmental and functional effects of TAZ-deficiency in different tissues, we generated isogenic TAZ knockout (TAZ- KO) and WT cardiomyocytes (CMs) and neural progenitor cells (NPCs) from CRISPR-edited induced pluripotent stem cells (iPSCs). In TAZ-KO CMs we discovered evidence of dysregulated mitophagy including dysmorphic mitochondria and mitochondrial cristae, differential expression of key autophagy-associated genes, and an inability of TAZ-deficient CMs to properly initiate stress-induced mitophagy. In TAZ-deficient NPCs we identified novel phenotypes including a reduction in CIV abundance and CIV activity in the CIII2&CIV2 intermediate complex. Interestingly, while CL acyl chain manipulation was unable to alter mitophagy defects in TAZ-KO CMs, we found that linoleic acid or oleic acid supplementation was able to partially restore CIV abundance in TAZ-deficient NPCs. Taken together, our results have implications for understanding the tissue-specific pathology of BTHS and potential for tissue-specific therapeutic targeting. Moreover, our results highlight an emerging role for mitophagy in the cardiac pathophysiology of BTHS and reveal a potential neuron-specific bioenergetic phenotype.

Physical Activity and the incidence of sepsis: A 10-year observational study among 4 million adults.

BACKGROUND: As the group at high risk for sepsis is increasing with the aging of the population, physical activity (PA), which has beneficial effects on various diseases, needs to be considered as a personalized prevention strategy for sepsis without direct anti-sepsis drug. PURPOSE: To examine the association between the amount of PA (based on intensity, duration, and frequency) and the incidence rates of sepsis and mortality after sepsis. METHODS: This was a large-scale, retrospective, longitudinal cohort study using data from the Korean National Health Insurance Service and the biennial general health screening program. The amount of PA self-reported at the time of the health screening was categorized as non-PA, mild (<500 metabolic equivalents [METs]-Min/Week), moderate (500-1000), severe (1000-1500), and extreme (≥1500). The multivariable regression model was adjusted for age, sex, income, body mass index, smoking, alcohol consumption, diabetes, hypertension, dyslipidemia, and chronic diseases. RESULTS: From 4,234,415 individuals who underwent a health screening in 2009, 3,929,165 subjects were selected after exclusion for wash-out period and a 1-year lag period, and then observed for the event of sepsis or all-cause death until December 2020. During a median 10.3 years of follow-up, 83,011 incidents of sepsis were detected. The moderate-PA group showed the lowest incidence (1.56/1000 person-years) and risk for sepsis, with an adjusted hazard ratio (aHR) of 0.73 (95% CI, 0.72-0.75, P < 0.001) compared with the non-PA group. The occurrence of sepsis among people aged ≥65 years and ex-smokers were significantly lower in the moderate-PA group (aHR; 0.77, 95% CI; 0.74-0.79; and 0.68, 0.64-0.71, respectively, Ps < 0.001). The long-term all-cause mortality after sepsis was significantly lower in the PA group than in the non-PA group (overall P = 0.003). CONCLUSIONS: Physical activity is associated with a lower risk of sepsis, especially in elderly people who have the highest incidence of sepsis. The protective effects of aerobic PA on sepsis might need to be incorporated with other interventions in sepsis guidelines through the accumulation of future studies.

Gamma-glutamyl transferase and the risk of all-cause and disease-specific mortality in patients with diabetes: A nationwide cohort study.

BACKGROUND: There exists a paucity of data regarding whether gamma-glutamyl transferase is associated with disease-specific mortality in patients with type 2 diabetes mellitus. This study aimed to investigate the association of serum gamma-glutamyl transferase levels with all-cause and disease-specific mortality in patients with diabetes mellitus using a Korean nationwide health-screening database. METHODS: A total of 9 687 066 patients without viral hepatitis or liver cirrhosis who underwent health examination in 2009 were included. These patients were divided into four groups according to sex-specific quartiles of serum gamma-glutamyl transferase levels. RESULTS: During a median follow-up period of 8.1 years, 222 242 deaths were identified. The all-cause mortality rate increased as the serum gamma-glutamyl transferase levels became higher (highest quartile vs lowest quartile: hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.55-1.59; p for trend <.001). Similar trends were observed for cardiovascular disease (HR, 1.57; 95% CI, 1.53-1.62), ischemic heart disease (HR, 1.40; 95% CI, 1.33-1.48), and stroke (HR, 1.72; 95% CI, 1.60-1.85) in the highest quartile, as compared with the lowest quartile (p for trend <.001). As the gamma-glutamyl transferase quartiles became higher, mortality rates related to cancer (HR, 1.56; 95% CI, 1.52-1.60), liver disease (HR, 9.42; 95% CI, 8.81-10.07), respiratory disease (HR, 1.55; 95% CI, 1.49-1.62), and infectious disease (HR, 1.73; 95% CI, 1.59-1.87) also increased in the highest quartile, compared with the lowest quartile (p for trend <.001). CONCLUSIONS: Serum gamma-glutamyl transferase levels may be useful for the risk assessment of all-cause and disease-specific mortality among patients with type 2 diabetes mellitus.

Prevalence and impact of depression and anxiety among older myocardial infarction survivors: A nationwide cohort study.

BACKGROUND: Depression and anxiety may be significant prognostic factors after myocardial infarction (MI). Thus, we investigated depression and anxiety prevalence among older MI survivors and their impact on mortality, stroke, and recurrent MI. METHODS: This population-based cohort study used the Korean National Health Insurance Service database for data concerning individuals aged 66 years who participated in the National Screening Program from 2009 to 2016. Overall, 11,721 individuals with MI history and 58,605 age- and sex-matched controls were included and followed up until 2019. The presence of depression and anxiety was assessed 2 years before and after participation in the program. Mortality and major adverse outcomes, defined as a composite outcome comprising mortality, stroke, and recurrent MI, were analyzed. RESULTS: Depression and anxiety prevalence among MI survivors was 20.4 % and 30.3 %, respectively. Crude odds ratios for depression and anxiety, compared with the control group, were 1.207 (1.148-1.269) and 1.078 (1.032-1.126), respectively. During the follow-up, individuals with depression, anxiety, or both showed increased hazard ratios (HRs) for mortality and major adverse outcomes; after adjustments, their HRs were 1.442 (1.182-1.759), 1.129 (0.960-1.328), and 1.498 (1.263-1.776), respectively, for mortality and 1.505 (1.289-1.758), 1.158 (1.021-1.314), and 1.530 (1.337-1.751), respectively, for major adverse outcomes. LIMITATIONS: Although this was a nationwide cohort study, the MI, depression, and anxiety diagnoses were based on diagnostic codes. CONCLUSIONS: Higher depression and anxiety prevalence was observed among older MI survivors. Depression and anxiety occurrence correlated with increased adverse clinical outcomes after adjustments.

The Relation Between Cigarette Smoking and Development of Sepsis: A 10-Year Follow-Up Study of Four Million Adults from the National Health Screening Program.

BACKGROUND: Sepsis remains a growing global health concern with soaring mortality and no direct anti-sepsis drug. Although smoking has distinct deleterious effects on chronic inflammatory illnesses and can impair immune function, a comprehensive analysis of the connection between sepsis and smoking is lacking. METHODS: This large-scale longitudinal cohort study retrospectively assessed adults aged ≥ 20 years who underwent national health checkups under the Korean National Health Insurance Service between January and December 2009 (N = 4,234,415) and were followed up for 10 years. Sepsis was identified based on the International Classification of Diseases, 10th Revision codes, and smoking status, including accumulated amount, was collected through a self-administered questionnaire. The Cox proportional hazard regression model was used, adjusting for age, sex, household income, body mass index, drinking, exercise, diabetes, hypertension, dyslipidemia, and chronic renal disease. RESULTS: After excluding cases with sepsis occurring before follow-up or after ≤ 1 year of follow-up, 3,881,958 participants, including non-smokers (N = 2,342,841), former smokers (N = 539,850), and active smokers (N = 999,267), were included. Compared to non-smokers, all active smokers (adjust hazard ratio: 1.41, 95% confidence interval 1.38-1.44) and former smokers (1.10, 1.07-1.14) with ≥ 20 pack-years exhibited a significantly higher risk of sepsis (p < 0.001). Smoking of ≥ 30 pack-years in former and active smokers groups significantly increased sepsis incidence (adjust hazard ratio [95% confidence interval] 1.34 [1.31-1.38], p < 0.001). CONCLUSIONS: Smoking is closely associated with the incidence of sepsis. Smoking cessation may help in the primary prevention of sepsis.

Risk of Depression according to Cumulative Exposure to a Low-Household Income Status in Individuals with Type 2 Diabetes Mellitus: A Nationwide Population- Based Study.

BACKGRUOUND: We aimed to identify the risk of incident depression according to cumulative exposure to a low-household income status in individuals with type 2 diabetes mellitus (T2DM). METHODS: For this retrospective longitudinal population-based cohort study, we used Korean National Health Insurance Service data from 2002 to 2018. Risk of depression was assessed according to cumulative exposure to low-household income status (defined as Medical Aid registration) during the previous 5 years among adults (aged ≥20 years) with T2DM and without baseline depression who underwent health examinations from 2009 to 2012 (n=2,027,317). RESULTS: During an average 6.23 years of follow-up, 401,175 incident depression cases occurred. Advance in cumulative number of years registered for medical aid during the previous 5 years from baseline was associated with an increased risk of depression in a dose-dependent manner (hazard ratio [HR], 1.44 [95% confidence interval (CI), 1.38 to 1.50]; HR, 1.40 [95% CI, 1.35 to 1.46]; HR, 1.42, [95% CI, 1.37 to 1.48]; HR, 1.46, [95% CI, 1.40 to 1.53]; HR, 1.69, [95% CI, 1.63 to 1.74] in groups with 1 to 5 exposed years, respectively). Insulin users exposed for 5 years to a low-household income state had the highest risk of depression among groups categorized by insulin use and duration of low-household income status. CONCLUSION: Cumulative duration of low-household income status, defined as medical aid registration, was associated with an increased risk of depression in a dose-response manner in individuals with T2DM.

Cumulative effect of impaired fasting glucose on the risk of dementia in middle-aged and elderly people: a nationwide cohort study.

The relationship between prediabetes and dementia remains controversial. We aimed to examine the association between cumulative exposure to impaired fasting glucose (IFG) and the risk of dementia in the general population. 1,463,066 middle-aged and elderly subjects who had had health examinations for four consecutive years were identified from a Korean nationwide population-based cohort database. IFG was defined as fasting blood glucose 100-125 mg/dL, and the risk of dementia-according to the number of IFG exposure (range 0-4)-was analyzed using the multivariable Cox proportional-hazards model. During the median 6.4 years of follow-up, 7614 cases of all-cause dementia, 5603 cases of Alzheimer's disease, and 1257 cases of vascular dementia occurred. There was a significant trend towards a higher risk of all-cause dementia (P for trend = 0.014) and Alzheimer's disease ( Pfor trend = 0.005) according to the cumulative exposure to IFG, but with a modest (approximately 7-14%) increase in the hazards. A significant stepwise increase in the risk of all-cause dementia and Alzheimer's disease was seen in non-obese subjects, whereas no significant association was observed in obese subjects. This study supports the association between prediabetes and incident dementia and emphasizes that even mild hyperglycemia should not be overlooked.

Association between regular physical activity and lower incidence of colorectal cancer in patients with diabetes mellitus: a nationwide cohort study.

AIM: The aim of this work was to investigate the association between changes in physical activity (PA) status and the development of colorectal cancer (CRC) in patients with diabetes. METHOD: This nationwide population study included 1 439 152 patients with diabetes who underwent a health screening provided by the Korean National Health Insurance Service between January 2009 and December 2012 and a follow-up screening after 2 years. Based on changes in PA status, participants were categorized into four groups: remained inactive, remained active, active-to-inactive and inactive-to-active. RESULTS: During the median follow-up period of 5.2 years, 38 244 new cases of CRC were diagnosed. Compared with the remained inactive group, among the three other groups, the remained active group had the lowest risk of CRC [adjusted hazard ratio (aHR) 0.93; 95% CI 0.90-0.96], followed by the inactive-to-active group (aHR 0.97; 95% CI 0.94-1.00) and active-to-inactive group (aHR 0.99; 95% CI 0.96-1.02), after adjusting for confounding variables (p = 0.0007). This reduction in cancer incidence in the remained active group was observed for both rectal cancer (aHR 0.87, 95% CI 0.79-0.95) and colon cancer (aHR 0.93, 95% CI 0.90-0.97), irrespective of sex. In terms of the intensity and amount of PA, moderate intensity PA was the most effective, and a positive correlation was found between the amount of PA and the reduction in CRC incidence. CONCLUSION: Regular PA was independently associated with a decreased risk of CRC in patients with diabetes. The intensity and amount of physical activity both play a role in reducing the risk.

Association between the fatty liver index and the risk of fracture among individuals over the age of 50 years: a nationwide population-based study.

Background and purpose: The association between fatty liver and fracture risk has not been firmly established. In this study, we investigated the relationship between the fatty liver index (FLI) and the incidence of fractures among individuals ≥50 years of age, using a nationwide population-based cohort. Methods: Data from the Korean National Health Insurance System between January 2009 and December 2019 were analyzed using the Cox proportional hazards model. Fatty liver status was defined using FLI. Newly diagnosed fractures were identified based on insurance claim data. Results: Among the 3,384,457 individuals who met our inclusion criteria over the study period, 444,203 cases of incident fractures were identified over a median follow-up of 10.3 years. On multivariate analysis, the risk of fracture was significantly higher among individuals with a higher FLI score compared to those with an FLI<30, with adjusted hazard ratio [aHR] and 95% confidence interval [CI] as follows: FLI 30-59 group, aHR 1.04 and 95% CI 1.03-1.05; and FLI ≥60 group, aHR 1.12 and 95% CI 1.10-1.13. A higher FLI was associated with a greater risk of hip (aHR 1.23 and 1.52 for the FLI 30-59 and FLI ≥60 group, respectively) and vertebral fracture (aHR 1.08 and 1.16 for the FLI 30-59 and FLI≥60 group, respectively). The association between the risk for fracture and FLI ≥60 was prominent for non-obese than obese individuals (aHR 1.25 and 95% CI, 1.22-1.27 versus 1.06 and 1.05-1.08, respectively). Conclusions: A high FLI is associated with an increased risk of hip and vertebral fractures among individuals ≥50 years of age, suggestive of an association between a higher FLI and osteoporotic fractures.

Differential risk of 23 site-specific incident cancers and cancer-related mortality among patients with metabolic dysfunction-associated fatty liver disease: a population-based cohort study with 9.7 million Korean subjects.

INTRODUCTION: Although an association between metabolic dysfunction-associated fatty liver disease (MAFLD) and cardiovascular disease or overall mortality has been reported, it is unclear whether there is an association between MAFLD and cancer incidence or mortality. We aimed to investigate the differential risk of all- and site-specific cancer incidence and mortality according to MAFLD subgroups categorized by additional etiologies of liver disease. METHODS: Using the Korean National Health Insurance Service database, we stratified the participants into three groups: (1) single-etiology MAFLD (S-MAFLD) or MAFLD of pure metabolic origin; (2) mixed-etiology MAFLD (M-MAFLD) or MAFLD with additional etiological factor(s) (i.e., concomitant liver diseases and/or heavy alcohol consumption); and (3) non-MAFLD. Hepatic steatosis and fibrosis were defined using the fatty liver index and the BARD score, respectively. Cox proportional hazards regression was performed to estimate the risk of cancer events. RESULTS: Among the 9,718,182 participants, the prevalence of S-MAFLD and M-MAFLD was 29.2% and 6.7%, respectively. During the median 8.3 years of follow-up, 510,330 (5.3%) individuals were newly diagnosed with cancer, and 122,774 (1.3%) cancer-related deaths occurred among the entire cohort. Compared with the non-MAFLD group, the risk of all-cancer incidence and mortality was slightly higher among patients in the S-MAFLD group (incidence, adjusted hazard ratio [aHR] = 1.03; 95% confidence interval [CI]: 1.02-1.04; mortality, aHR = 1.06; 95% CI: 1.04-1.08) and highest among patients with M-MAFLD group (incidence, aHR = 1.31; 95% CI: 1.29-1.32; mortality, aHR = 1.45; 95% CI: 1.42-1.48, respectively). The M-MAFLD with fibrosis group (BARD score ≥ 2) showed the highest relative risk of all-cancer incidence (aHR = 1.38, 95% CI = 1.36-1.39), followed by the M-MAFLD without fibrosis group (aHR = 1.09, 95% CI = 1.06-1.11). Similar trends were observed for cancer-related mortality. CONCLUSIONS: MAFLD classification, by applying additional etiologies other than pure metabolic origin, can be used to identify a subgroup of patients with poor cancer-related outcomes.

Low Household Income Status and Death from Pneumonia in People with Type 2 Diabetes Mellitus: A Nationwide Study.

BACKGRUOUND: We explored the risk of death from pneumonia according to cumulative duration in low household income state (LHIS) among adults with type 2 diabetes mellitus (T2DM). METHODS: Using Korean National Health Insurance Service data (2002 to 2018), the hazards of mortality from pneumonia were analyzed according to duration in LHIS (being registered to Medical Aid) during the 5 years before baseline (0, 1-4, and 5 years) among adults with T2DM who underwent health examinations between 2009 and 2012 (n=2,503,581). Hazards of outcomes were also compared in six groups categorized by insulin use and duration in LHIS. RESULTS: During a median 7.18 years, 12,245 deaths from pneumonia occurred. Individuals who had been exposed to LHIS had higher hazards of death from pneumonia in a dose-response manner (hazard ratio [HR], 1.726; 95% confidence interval [CI], 1.568 to 1.899 and HR, 4.686; 95% CI, 3.948 to 5.562 in those exposed for 1-4 and 5 years, respectively) compared to the non-exposed reference. Insulin users exposed for 5 years to LHIS exhibited the highest outcome hazard among six groups categorized by insulin use and duration in LHIS. CONCLUSION: Among adults with T2DM, cumulative duration in LHIS may predict increased risks of mortality from pneumonia in a graded dose-response manner. Insulin users with the longest duration in LHIS might be the group most vulnerable to death from pneumonia among adults with T2DM.

Association between fatty liver index and risk of end-stage renal disease stratified by kidney function in patients with type 2 diabetes: A nationwide population-based study.

OBJECTIVE: The effects of nonalcoholic fatty liver disease on the risk of end-stage renal disease (ESRD) remain unclear. We investigated the association between the fatty liver index (FLI) and risk of ESRD in patients with type 2 diabetes. METHODS: This population-based observational cohort study enrolled patients with diabetes who underwent health screening between 2009 and 2012 and utilized data from the Korean National Health Insurance Services. The FLI functioned as a surrogate marker for the presence of hepatic steatosis. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m² calculated using the Modification of Diet in Renal Disease equation. We performed Cox proportional hazards regression. RESULTS: Incident ESRD developed in 19,476 of 1,900,598 patients with type 2 diabetes during a median follow-up of 7.2 years. After adjusting for conventional risk factors, patients with high FLI scores had a higher risk for ESRD: FLI, 30-59 [hazard ratio (HR) = 1.124; 95% confidence interval (CI), 1.083-1.166]; FLI ≥ 60 [HR = 1.278; 95% CI, 1.217-1.343] compared with those with FLI < 30. The association between a high FLI score (≥ 60) and incident ESRD was more prominent in women than in men (male, FLI ≥60: HR, 1.106; 95% CI = 1.041-1.176 and female, FLI ≥ 60: HR, 1.835; 95% CI = 1.689-1.995). The association between a high FLI score (≥ 60) and the risk of ESRD differed according to baseline kidney function. High FLI scores increased the risk of ESRD (HR = 1.268; 95% CI, 1.198-1.342) in patients with CKD at baseline. CONCLUSION: High FLI scores are associated with a greater risk of ESRD in patients with type 2 diabetes with CKD at baseline. Close monitoring and appropriate management of hepatic steatosis may aid in preventing the progression of kidney dysfunction in patients with type 2 diabetes and CKD.

Glucose Control in Korean Patients with Type 2 Diabetes Mellitus according to Body Mass Index.

Background: The prevalence of type 2 diabetes mellitus has continued to rise. Although many studies have focused on the connection between weight loss and glucose control, only a few studies have investigated the association between body mass index (BMI) and glucose control status. We examined the association between glucose control and obesity. Methods: We analyzed 3,042 participants with diabetes mellitus who were aged ≥19 years when they participated in the 2014 to 2018 Korean National Health and Nutrition Examination Survey. The participants were divided into four groups according to their BMI (<18.5, 18.5-23, 23-25, and ≥25 kg/m2). We used guidelines from the Korean Diabetes Association to compare the glucose control in those groups, with a cross-sectional design, multivariable logistic regression, and glycosylated hemoglobin <6.5% as the reference. Results: Overweight males aged ≥60 years had a high odds ratio (OR) for degraded glucose control (OR, 1.706; 95% confidence interval [CI], 1.151 to 2.527). Among obese females, those in the ≥60 years age group showed an increased OR for uncontrolled diabetes (OR, 1.516; 95% CI, 1.025 to 1.892). Moreover, in females, the OR for uncontrolled diabetes tended to increase as the BMI increased (P=0.017). Conclusion: Obesity is associated with uncontrolled diabetes in female patients with diabetes who are aged ≥60 years. Physicians should closely monitor this group for diabetes control.

Lean or diabetic subtypes predict increased all-cause and disease-specific mortality in metabolic-associated fatty liver disease.

BACKGROUND: Metabolic-associated fatty liver disease (MAFLD) encompasses diverse disease groups with potentially heterogeneous clinical outcomes. We investigated the risk of all-cause and disease-specific mortality in MAFLD subgroups. METHODS: Using the Korean National Health Insurance Service database, participants were divided into four subgroups: no MAFLD, MAFLD-diabetes, MAFLD-overweight/obese, and MAFLD-lean. Hazard ratios (HRs) and 95% confidence interval (CI) values for all-cause and disease-specific mortality according to MAFLD subgroups were analyzed using Cox proportional hazards models. RESULTS: Among 9,935,314 participants, those with MAFLD-diabetes showed the highest risk of all-cause and disease-specific mortality. The HRs (95% CI) for all-cause mortality were 1.61 (1.59-1.63), 1.36 (1.34-1.38), and 1.19 (1.18-1.20) in the MAFLD-diabetes, MAFLD-lean, and MAFLD-overweight/obese groups, respectively. The magnitude of cardiovascular disease and cancer-related risk showed the same pattern. The risk of liver-related mortality in the MAFLD-lean group (HR: 2.84, 95% CI: 2.72-2.97) was comparable with that in the MAFLD-diabetes group (HR: 2.85, 95% CI: 2.75-2.95). When stratified by body mass index, liver-related mortality was the highest in MAFLD-lean individuals in the underweight group (HR, 5.03, 95% CI: 4.23-5.97). CONCLUSIONS: The MAFLD-lean and MAFLD-diabetes groups had a higher risk of all-cause and disease-specific mortality than did the MAFLD-overweight/obese group. Classifying MAFLD subgroups based on metabolic phenotypes might help risk stratification of patients with MAFLD.

Impact of albuminuria on the various causes of death in diabetic patients: a nationwide population-based study.

Diabetes mellitus (DM) is a well-known risk factor for mortality, and the risk is exacerbated by coexisting diabetic kidney disease (DKD). We aimed to explore the impact of DM on each cause of mortality according to kidney function and the presence of albuminuria. Data on subjects with DM were extracted from the Nationwide Health Insurance Database of South Korea between 2009 and 2012. Subjects were divided by eGFR and albuminuria into five groups. To evaluate the risk of diabetes, we used the Cox proportional hazards model. A total of 2,614,662 patients were enrolled in this study. Most causes of death showed a higher incidence in an advanced stage of DKD. In addition to all-cause mortality and cardiovascular death, the risk of death from neoplasms and diseases of the endocrine, respiratory, and digestive systems is increased by albuminuria. The synergistic effect of a reduced eGFR and the presence of albuminuria was prominent in death from circulatory diseases, and endocrine and metabolic diseases. The risk for mortality was different according to the stage of DKD. Even in patients with a favorable eGFR, the presence of albuminuria significantly increased the risk for mortality, especially that due to cardiovascular causes.

Gamma-glutamyl transferase and risk of all-cause and disease-specific mortality: a nationwide cohort study.

Population-based data regarding the prognostic implication of gamma-glutamyl transferase (GGT) have been inconsistent. We examined the association of GGT with all-cause and disease-specific mortality. Using the Korean nationwide database, we included 9,687,066 subjects without viral hepatitis or cirrhosis who underwent a health examination in 2009. Subjects were classified into three groups by sex-specific tertile of serum GGT levels. The underlying causes of death were classified by 10th Revision of the International Classification of Diseases codes. During the median follow-up period of 8.3 years, 460,699 deaths were identified. All-cause mortality increased as serum GGT levels became higher (hazard ratio [HR], 95% confidence interval [CI] 1.05, 1.04-1.05 in the middle tertile, and 1.33, 1.32-1.34 in the high tertile) compared to the low tertile of serum GGT levels. Similar trends were observed for cardiovascular disease (CVD) (HR, 95% CI 1.07, 1.05-1.09 in the middle tertile, 1.29, 1.26-1.31 in the high tertile), cancer (HR, 95% CI 1.08, 1.07-1.10 in the middle tertile, 1.38, 1.36-1.39 in the high tertile), respiratory disease (HR, 95% CI 1.10, 1.08-1.13 in the middle tertile, 1.39, 1.35-1.43 in the high tertile), and liver disease mortality (HR, 95% CI 1.74, 1.66-1.83 in the middle tertile, 6.73, 6.46-7.01 in the high tertile). Regardless of smoking, alcohol consumption and history of previous CVD and cancer, a higher serum GGT levels were associated with a higher risk of mortality. Serum GGT levels may be useful for risk assessment of all-cause and disease-specific mortality in general population.

The association of fatty liver index and BARD score with all-cause and cause-specific mortality in patients with type 2 diabetes mellitus: a nationwide population-based study.

BACKGROUND: Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) commonly coexist. However, NAFLD's effect on mortality in Asian patients with type 2 diabetes awaits full elucidation. Therefore, we examined NAFLD-related all-cause and cause-specific mortality in a nationwide Asian population with type 2 diabetes. METHODS: We included patients who had undergone general health checkups between 2009 and 2012 using the National Health Insurance Service database linked to death-certificate data. Hepatic steatosis was defined as a fatty liver index (FLI) ≥ 60, and advanced hepatic fibrosis was determined using the BARD score. FINDINGS: During the follow-up period of 8.1 years, 222,242 deaths occurred, with a mortality rate of 14.3/1000 person-years. An FLI ≥ 60 was significantly associated with increased risks of all-cause and cause-specific mortality including cardiovascular disease (CVD)-, cancer-, and liver disease (FLI ≥ 60: hazard ratio [HR] = 1.02, 95% confidence interval [CI] 1.01-1.03 for all-cause; 1.07, 1.04-1.10 for CVD; 1.12, 1.09-1.14 for cancer; and 2.63, 2.50-2.77 for liver disease). Those with an FLI ≥ 60 and fibrosis (BARD ≥ 2) exhibited increased risks of all-cause (HR, 95% CI 1.11, 1.10-1.12), CVD- (HR, 95% CI 1.11, 1.09-1.14), cancer- (HR, 95% CI 1.17, 1.15-1.19), and liver disease-related (HR, 95% CI 2.38, 2.29-2.49) mortality. CONCLUSION: Hepatic steatosis and advanced fibrosis were significantly associated with risks of overall and cause-specific mortality in patients with type 2 diabetes. Our results provide evidence that determining the presence of hepatic steatosis and/or fibrosis potentially plays a role in risk stratification of mortality outcomes in patients with type 2 diabetes mellitus.

Impact of mental disorders on the risk of atrial fibrillation in patients with diabetes mellitus: a nationwide population-based study.

BACKGROUND: It is unclear whether mental disorders are an independent risk factor for atrial fibrillation (AF) in patients with diabetes. We aimed to investigate whether patients with diabetes who have mental disorders have an increased risk for AF. METHODS: Using the Korea National Health Insurance Service database, we enrolled 2,512,690 patients diagnosed with diabetes without AF between 2009 and 2012. We assessed five mental disorders: depression, insomnia, anxiety, bipolar disorder, and schizophrenia. Newly diagnosed AF was identified during the follow-up period, and multivariate Cox regression analysis was performed. RESULTS: Among the 2,512,690 patients (mean age 57.2 ± 12.3 years; 60.1% men), 828,929 (33.0%) had mental disorders. Among the five mental disorders, anxiety (68.1%) was the most common, followed by insomnia (40.0%). During a median follow-up duration of 7.1 years, new-onset AF was diagnosed in 79,525 patients (4.66 per 1,000 person-years). Patients with diabetes who had mental disorders showed a higher risk for AF (adjusted hazard ratio [HR] 1.19; 95% confidence interval [CI] 1.17-1.21; p-value < 0.001). Depression, insomnia, and anxiety were significantly associated with higher risk for AF (adjusted HR [95% CI]: 1.15 [1.12-1.17], 1.15 [1.13-1.18], and 1.19 [1.67-1.21], respectively; all p-values < 0.001), whereas bipolar disorder and schizophrenia were not. CONCLUSIONS: Mental disorders, especially depression, insomnia, and anxiety, were associated with an increased risk for AF in patients with diabetes. Greater awareness with a prompt diagnosis of AF should be considered for patients with both DM and mental disorders.

Comorbidities associated with high-risk obstructive sleep apnea based on the STOP-BANG questionnaire: a nationwide population-based study.

BACKGROUND/AIMS: We investigated the prevalence, associated factors, and comorbidities of high-risk obstructive sleep apnea (OSA) as determined by the STOP-BANG questionnaire in a Korean adult population. METHODS: Data were obtained from 7,650 adults (aged ≥ 40 years) who participated in the Korea National Health and Nutrition Examination Survey (2019-2020). Multiple logistic regression analyses were used to evaluate the association of socioeconomic status, lifestyle related factors, and comorbidities with high-risk OSA (STOP-BANG score, 5-8). RESULTS: The prevalence of high-risk OSA according to the STOP-BANG questionnaire was 12.0 %. Older age, male, current smoking, heavy alcohol consumption, and more comorbidities were associated with higher STOP-BANG scores. In multivariable adjusted analysis, diabetes mellitus (DM) (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.25 to 1.97), hypertension (OR, 4.81; 95% CI, 3.88 to 5.97), and obesity (OR, 2.02; 95% CI, 1.60 to 2.56) were associated with high risk of OSA, and when hypertension, DM, and obesity were combined, the risk increased synergistically (OR, 3.88; 95% CI, 2.94 to 5.11). CONCLUSION: According to the STOP-BANG questionnaire, the high risk of OSA was more common in males, and was associated with chronic metabolic disease, particularly in those with DM, hypertension, and obesity combined. Active OSA screening, prevention, and management may be beneficial to improving health outcomes related to OSA in these populations.

Association of comorbid mental disorders with cardiovascular disease risk in patients with type 2 diabetes: A nationwide cohort study.

OBJECTIVE: To examine the association between comorbid mental disorders and cardiovascular disease (CVD) risk among patients with type 2 diabetes. METHOD: This retrospective cohort study was conducted using the claims data of 2,227,394 South Korean patients with type 2 diabetes. We analyzed the occurrence of CVD including myocardial infarction (MI) and ischemic stroke, CVD-specific mortality, and all-cause mortality according to comorbid mental disorders including depressive disorders, bipolar and related disorders, schizophrenia spectrum disorders, insomnia, and anxiety disorders. RESULTS: Among the patients, 9.1% had a comorbid mental disorder. The adjusted hazard ratios (aHR) for MI, ischemic stroke, CVD-specific mortality, and all-cause mortality in patients with any mental disorder were 1.20 (95% CI, 1.17-1.24), 1.13 (95% CI, 1.11-1.16), 1.16 (95% CI, 1.12-1.20), and 1.21 (95% CI, 1.19-1.23), respectively. Each mental disorder increased the risk of all outcomes, particularly bipolar and related disorders and schizophrenia spectrum disorders. CONCLUSION: Comorbid mental disorders increased the CVD risk in patients with type 2 diabetes, with significantly increased risks associated with schizophrenia spectrum disorders (aHR: 1.27 for MI and 1.50 for ischemic stroke) and bipolar and related disorders (aHR: 1.27 for MI and 1.45 for ischemic stroke).