SECRETED TRYPTOPHANYL-tRNA SYNTHETASE 1 IS A PROGNOSTIC MARKER IN SEPSIS PATIENTS WITHOUT MONOCYTOPENIA.

ABSTRACT: Objective: This study aimed to test whether the prognostic value of tryptophanyl-tRNA synthetase 1 (WARS1) for 28-day mortality in patients with sepsis was affected by monocytopenia. Methods: A prospective analysis of retrospectively collected samples from 74 sepsis patients was performed. WARS1, C-reactive protein (CRP), and procalcitonin were measured at admission and 24 and 72 h after admission. The prognostic value of WARS1, CRP, and procalcitonin for 28-day mortality was compared using repeated measures analysis of variance and the area under the receiver operating characteristic curve (AUROC). All analyses were performed in patients with or without monocytopenia, defined as an absolute monocyte count less than 0.1 × 10 9 cells/L. Results: WARS1 levels differed significantly between survivors and nonsurvivors when all patients and patients without monocytopenia were assessed ( P = 0.008, P < 0.001, respectively). In contrast, the WARS1 level did not differ between survivors and nonsurvivors with monocytopenia. C-reactive protein and procalcitonin levels were not different between survivors and nonsurvivors regardless of whether they had monocytopenia. The AUROCs of WARS1 at admission and 24 h for mortality were significantly higher in patients without monocytopenia (0.830, 0.818) than in patients with monocytopenia (0.232, 0.196; P < 0.001, both). When patients without monocytopenia were analyzed, the AUROCs of WARS1 for mortality were 0.830 and 0.818 at admission and 24 h, respectively, which were significantly higher than those of CRP (0.586, 0.653) and procalcitonin (0.456, 0.453) at the same time points ( P = 0.024 and 0.034, respectively). Conclusion: WARS1 is a useful biomarker for prognosis in sepsis patients without monocytopenia.

Combination Therapy of Niacin and Apocynin Attenuates Lung Injury During Sepsis in Rats.

INTRODUCTION: Oxidative stress contributes to tissue injury through reactive oxygen species-dependent signaling pathways during sepsis. We studied therapeutic benefits of the combination therapy of niacin, which increased reduced glutathione levels, and apocynin, which suppressed reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activity, in septic rats. MATERIALS AND METHODS: Polymicrobial sepsis was induced through cecal ligation and puncture (CLP) with antibiotics in male Sprague-Dawley rats (n = 189). The rats were randomly divided into sham, CLP, CLP + niacin, CLP + apocynin, and CLP + niacin + apocynin groups. Six hours after CLP, vehicle, niacin (360 mg/kg through the orogastric tube), and/or apocynin (20 mg/kg through intraperitoneal injection) were administered. The occurrence of mortality for 72 h after CLP was observed. Next, a separate set of animals was euthanized at 24 h post-CLP for lung tissue analyses. RESULTS: Combination therapy with niacin and apocynin significantly improved survival in rats with sepsis (75.0% versus 28.8%, P = 0.006) but monotherapy with niacin or apocynin did not. Monotherapy with niacin and apocynin appeared to increase NADPH levels and decrease Nox levels and activity, respectively, but failed to show statistical significances. However, combination therapy significantly decreased Nox levels and activity, increased NADPH and glutathione levels, decreased intranuclear nuclear factor-κB (NF-κB) p65 levels, reduced inflammatory cytokine expression and malondialdehyde levels, and attenuated histological lung injuries. CONCLUSIONS: Combination therapy with niacin and apocynin synergistically attenuated lung injuries and improved survival in rats with sepsis through niacin-induced glutathione redox cycle activation and apocynin-induced Nox suppression.

Trends and Patterns of Cancer Burdens by Region and Income Level in Korea: A National Representative Big Data Analysis.

PURPOSE: This study aimed to elucidate the trends and characteristics of the cancer burden in Korea by cancer site, region, and income level. Materials and Methods: Korean National Burden of Disease research methodology was applied to measure the cancer burden in Korea from 2008 to 2018. The cause of death and national health insurance claims data were obtained from Statistics Korea and the National Health Insurance Service, respectively. An incidence-based approach was applied to calculate the disability-adjusted life-years, which is a summary measure of population health. RESULTS: In the past decade, the cancer burden in Korea increased from 2,088 to 2,457 person-years per 100,000 population. Among the cancer burden, the years of life lost decreased, and the years lived with disabilities increased. Cancers of the trachea, bronchus, and lung had the highest disease burden, followed by those of the stomach, colon and rectum, liver, and breast. CONCLUSION: The findings of this study can provide valuable quantitative data for prioritizing and evaluating cancer prevention strategies and implementing cancer policies. Estimating the difference in cancer burden according to region and income level within a country can yield useful data to understand the nature of the cancer burden and scale of the problem. In addition, the results of this study provide a better understanding of the causes of cancer patterns, thereby generating new hypotheses regarding its pathogenesis.

Burden of Cancer Due to Cigarette Smoking and Alcohol Consumption in Korea.

This study aimed to estimate the burden of cancer in Koreans attributable to smoking and alcohol consumption using disability-adjusted life years and population attributable fractions. We estimated the burden of 12 cancers due to simultaneous and independent smoking and alcohol exposure in Koreans aged ≥40 years. In men, the cancer burden attributable to the combined risk factors, smoking alone, and alcohol consumption alone were 9.5, 14.8, and 6.1%, respectively; the corresponding values for women were 1.1, 2.5, and 2.7%, respectively. In men, tracheal, bronchial, and lung cancers were the most common cancer types. The disease burden may have been reduced by 16.8, 32.3, and 4.1% in the absence of the combined risk factors, smoking alone, and alcohol consumption alone, respectively. Our findings suggest that risk factor-based intervention may have the greatest preventative effect for lung cancer among all cancers in men. Our real-world data methodology could provide further evidence-based methods to explore and facilitate effective health promotion interventions for specific target groups and may lay the foundation for the establishment of healthcare services according to population subgroups or regional characteristics.

The prevalence, incidence, and admission rate of diagnosed schizophrenia spectrum disorders in Korea, 2008-2017: A nationwide population-based study using claims big data analysis.

This study estimated the prevalence and incidence rate of schizophrenia, schizotypal, and delusional disorders (SSDD) in Korea from 2008 to 2017 and analyzed the hospital admission rate, re-admission rate, and hospitalization period. It used the Korean nationwide National Health Insurance Service claims database. SSDD patients who had at least one visit to Korea's primary, secondary, or tertiary referral hospitals with a diagnosis of SSDD, according to the International Classification of Diseases, 10th Revision (ICD-10), were identified as SSDD cases if coded as F20-F29. Data were analyzed using frequency statistics. Results showed that the 12-month prevalence rate of SSDD increased steadily from 0.40% in 2008 to 0.45% in 2017. Analysis of the three-year cumulative prevalence rate of SSDD showed an increase from 0.51% in 2011 to 0.54% in 2017. In 2017, the five-year cumulative prevalence rate was 0.61%, and the 10-year cumulative prevalence rate was 0.75%. The hospital admission rate among SSDD patients decreased from 2008 (30.04%) to 2017 (28.53%). The incidence of SSDD was 0.05% and no yearly change was observed. The proportion of SSDD inpatients whose first hospital visit resulted in immediate hospitalization was 22.4% in 2017. Epidemiological indicators such as prevalence, incidence, and hospitalization rate play an important role in planning social and financial resource allocation. Therefore, efforts to produce more accurate epidemiological indicators are very important and this study's findings could have a significant social impact.

Circulating mitochondrial N-formyl peptides contribute to secondary nosocomial infection in patients with septic shock.

Secondary infections typically worsen outcomes of patients recovering from septic shock. Neutrophil [polymorphonuclear leukocytes (PMNs)] migration to secondarily inoculated sites may play a key role in inhibiting progression from local bacterial inoculation to secondary infection. Mitochondrial N-formyl peptide (mtFP) occupancy of formyl peptide receptor-1 (FPR1) has been shown to suppress PMN chemotaxis. Therefore, we studied the association between circulating mtFPs and the development of secondary infection in patients with septic shock. We collected clinical data and plasma samples from patients with septic shock admitted to the intensive care unit for longer than 72 h. Impacts of circulating nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) upon clinical outcomes were analyzed. Next, the role of ND6 in PMN chemotaxis was investigated using isolated human PMNs. Studying plasma samples from 97 patients with septic shock, we found that circulating ND6 levels at admission were independently and highly associated with the development of secondary infection (odds ratio = 30.317, 95% CI: 2.904 to 316.407, P = 0.004) and increased 90-d mortality (odds ratio = 1.572, 95% CI: 1.002 to 2.465, P = 0.049). In ex vivo experiments, ND6 pretreatment suppressed FPR1-mediated PMN chemotactic responses to bacterial peptides in the presence of multiple cytokines and chemokines, despite increased nondirectional PMN movements. Circulating mtFPs appear to contribute to the development of secondary infection and increased mortality in patients with septic shock who survive their early hyperinflammatory phase. The increased susceptibility to secondary infection is probably partly mediated by the suppression of FPR1-mediated PMN chemotaxis to secondary infected sites.

Associations Between Private Health Insurance and Medical Care Utilization for Musculoskeletal Disorders: Using the Korea Health Panel Survey Data for 2014 to 2015.

In South Korea, people may increase their medical coverage by purchasing private health insurance to augment low coverage provided by the National Health Insurance (NHI). Frequent and excessive use of medical care by those with private health insurance is an issue, especially for musculoskeletal disorders that require excessive care and contribute to moral hazard. In South Korea, since private health insurance is structurally linked to the scope of coverage with public health insurance, this increased use of medical care may adversely affect public health insurance finances. This study aimed to analyze the effects of private health insurance on medical care use for patients with musculoskeletal disorders. We used the Korea Health Panel 2014 to 2015 data that included 5622 participants who used medical care for musculoskeletal disorders in 2015. Two groups were created: those who purchased private health insurance (n = 3588) and those without private insurance (n = 2034). We compared their medical utilization using logistic regression, negative binomial regression, and multiple linear regression to determine the associations of private health insurance with medical care use. Medical expenditures by private health insurance purchasers were higher than those of non-purchasers for outpatient care (P < .001), but no differences were found for inpatient care. Our findings suggest that the expansion of private health insurance further burdened the NHI financially, ultimately increasing the burden of medical expenses for the population. Research should implement demonstration studies with different groups of diseases.

Projecting the prevalence of obesity in South Korea through 2040: a microsimulation modelling approach.

OBJECTIVE: To project the prevalence of obesity in 2040 among individuals 19 years and older in South Korea. DESIGN, SETTING, AND PARTICIPANTS: Using the 'Population Health Model-body mass index' (BMI) microsimulation model, the prevalence of obesity in Korean adults 19 years and older was projected until 2040. The model integrated individual survey data from the Korea Health Panel Survey of 2011 and 2012, population statistics based on resident registration, population projections and complete life tables categorised by sex and age. Birth rate, life expectancy and international migration were based on a medium growth scenario. The base population of Korean adults in 2012, devised through data aggregation, was 39 842 730. The prediction equations were formulated using BMI as the dependent variable; the individual's sex, age, smoking status, physical activity and preceding year's BMI were used as predictive factors. OUTCOME MEASURE: BMI categorised by sex. RESULTS: The median BMI for Korean adults in 2040 was expected to be 23.55 kg/m2 (23.97 and 23.17 kg/m2 for men and women, respectively). According to the Korean BMI classification, 70.05% of all adults were expected to be 'preobese' (ie, have BMIs 23-24.9 kg/m2) by 2040 (81.23% of men and 59.07% of women) and 24.88% to be 'normal'. CONCLUSIONS: We explored the possibility of applying and expanding on the concept of microsimulation in the field of healthcare by combining data sources available in Korea and found that more than half of the adults in this study population will be preobese, and the proportions of 'obesity' and 'normal' will decrease compared with those in 2012. The results of our study will aid in devising healthy strategies and spreading public awareness for preventing this condition.

Delayed endoscopy is associated with increased mortality in upper gastrointestinal hemorrhage.

OBJECTIVES: To determine the association between delayed (>24 h) endoscopy and hospital mortality in patients with upper gastrointestinal hemorrhage (UGIH). METHODS: We retrospectively analyzed all adult patients with UGIH who underwent endoscopy in a single emergency room for 2 years. The primary exposure was defined as >24 h from the ED visit to the first endoscopy. The primary outcome was defined as all cause hospital mortality. Secondary outcomes were intensive care unit admission rate, ED length of stay, and hospital length of stay. RESULTS: Among 1101 patients enrolled, 898 received endoscopy within 24 h (early group) and 203 received endoscopy after 24 h (delayed group). The hospital mortality of early and delayed group was 2.8% and 6.4%, respectively (unadjusted relative risk [RR] 2.30: 95% CI, 1.20-4.42, p = 0.012). This was significant after adjusting covariates including AIMS65 and Glasgow-Blatchford score (adjusted RR 2.23: 95% CI, 1.18-4.20, p = 0.013). Intensive care unit admission rate was not different between two groups. ED and hospital length of stay were significantly longer in delayed group. CONCLUSIONS: Endoscopy performed after 24 h was associated with increased hospital mortality in UGIH. Patients in the delayed group stayed longer in the ED and in the hospital.

Niacin and Selenium Attenuate Brain Injury After Cardiac Arrest in Rats by Up-Regulating DJ-1-Akt Signaling.

OBJECTIVES: To determine neuroprotective effects and mechanism of the combination therapy of niacin and selenium in cardiac arrest rats. DESIGN: Prospective laboratory study. SETTING: University laboratory. SUBJECTS: Rat cortex neurons and male Sprague-Dawley rats (n = 68). INTERVENTIONS: In rat cortex neurons underwent 90 minutes of oxygen-glucose deprivation and 22.5 hours of reoxygenation, effects of the combination therapy of niacin (0.9 mM) and selenium (1.5 µM) were investigated. The role of DJ-1 was determined using DJ-1 knockdown cells. In cardiac arrest rats, posttreatment effects of the combination therapy of niacin (360 mg/kg) and selenium (60 µg/kg) were evaluated. MEASUREMENTS AND MAIN RESULTS: In oxygen-glucose deprivation and 22.5 hours of reoxygenation cells, combination therapy synergistically activated the glutathione redox cycle by a niacin-induced increase in glutathione reductase and a selenium-induced increase in glutathione peroxidase activities and reduced hydrogen peroxide level. It increased phosphorylated Akt and intranuclear Nuclear factor erythroid 2-related factor 2 expression and attenuated neuronal injury. However, these benefits were negated by DJ-1 knockdown. In cardiac arrest rats, combination therapy increased DJ-1, phosphorylated Akt, and intranuclear nuclear factor erythroid 2-related factor 2 expression, suppressed caspase 3 cleavage, and attenuated histologic injury in the brain tissues. It also improved the 7-day Neurologic Deficit Scales from 71.5 (66.0-74.0) to 77.0 (74.-80.0) (p = 0.02). CONCLUSIONS: The combination therapy of clinically relevant doses of niacin and selenium attenuated brain injury and improved neurologic outcome in cardiac arrest rats. Its benefits were associated with reactive oxygen species reduction and subsequent DJ-1-Akt signaling up-regulation.

Plasma glutathione reductase activity and prognosis of septic shock.

BACKGROUND: Our aim was to investigate whether plasma glutathione reductase (GR) activity is well correlated with the erythrocyte-reduced glutathione (GSH)/glutathione disulfide (GSSG) ratio and is associated with the mortality of septic shock. MATERIALS AND METHODS: This study was conducted on male Sprague-Dawley rats and patients admitted to the intensive care unit with septic shock. To induce endotoxemia in rats, vehicle or lipopolysaccharide (LPS) at dosages of 5 or 10 mg/kg were injected into a tail vein. Animals were then euthanized 6 h post-LPS. Based on the 28-d mortality, the enrolled patients were divided into the survivors and nonsurvivors. We obtained blood samples from patients at admission (0 h) and 24 h after admission to the intensive care unit. RESULTS: In endotoxemic rats, the erythrocyte GSH/GSSG ratio, erythrocyte GR activity, and plasma GR activity in the 10 mg/kg of LPS group were lower than those in the sham and 5 mg/kg of LPS groups. In patients with septic shock, decrease in plasma GR activity at 24 h was independently associated with an increase in 28-d mortality (odds ratio, 0.828; 95% confidence interval, 0.690-0.992, P = 0.041). Plasma GR activity was correlated with erythrocyte GR activity (Spearman ρ = 0.549, P < 0.001) and the erythrocyte GSH/GSSG ratio (rho = 0.367, P = 0.009) at 24 h. CONCLUSIONS: Plasma GR activity was well correlated with erythrocyte GR activity and the erythrocyte GSH/GSSG ratio, and a decrease in plasma GR activity was associated with an increase in the mortality of septic shock patients.

Niacin and Selenium Attenuate Sepsis-Induced Lung Injury by Up-Regulating Nuclear Factor Erythroid 2-Related Factor 2 Signaling.

OBJECTIVES: To determine whether the combination therapy of niacin and selenium attenuates lung injury and improves survival during sepsis in rats and whether its benefits are associated with the activation of the glutathione redox cycle and up-regulation of nuclear factor erythroid 2-related factor 2. DESIGN: Prospective laboratory study. SETTING: University laboratory. SUBJECTS: Human lung microvascular endothelial cells and male Sprague-Dawley rats (n = 291). INTERVENTION: In lipopolysaccharide-exposed cells, the dose-related effects of niacin and selenium were assessed, and the therapeutic effects of the combination therapy of niacin (0.9 mM) and selenium (1.5 µM) were evaluated. The role of nuclear factor erythroid 2-related factor 2 was determined using nuclear factor erythroid 2-related factor 2 knockdown cells. In endotoxemic and cecal ligation and puncture with antibiotics rats, the therapeutic effects of the posttreatments of clinically relevant doses of niacin (360 mg/kg) and selenium (60 µg/kg) were evaluated. MEASUREMENTS AND MAIN RESULTS: Combination therapy reduced the hydrogen peroxide level via the synergistic activation of the glutathione redox cycle, which involves niacin-induced increases in glutathione reductase activity, and reduced the glutathione level and a selenium-induced increase in glutathione peroxidase activity. Combination therapy contributed to the up-regulation of nuclear factor erythroid 2-related factor 2, enhancement of glutathione synthesis, and down-regulation of nuclear factor κB signaling, but nuclear factor erythroid 2-related factor 2 knockdown inhibited the enhancement of glutathione synthesis and down-regulation of the nuclear factor κB pathway. The therapeutic effects of combination therapy on endotoxemic rats were consistent with those on lipopolysaccharide-exposed cells. In addition, the posttreatment of combination therapy attenuated lung injury and improved survival in endotoxemic and cecal ligation and puncture with antibiotics rats. However, individual therapies of niacin or selenium failed to achieve these benefits. CONCLUSIONS: The combination therapy of niacin and selenium attenuated lung injury and improved survival during sepsis. Its therapeutic benefits were associated with the synergistic activation of the glutathione redox cycle, reduction of hydrogen peroxide level, and up-regulation of nuclear factor erythroid 2-related factor 2.

The therapeutic effect and mechanism of niacin on acute lung injury in a rat model of hemorrhagic shock: Down-regulation of the reactive oxygen species-dependent nuclear factor κB pathway.

BACKGROUND: The purpose of the current study was to investigate the protective effect of niacin on acute lung injury by the down-regulation of the nuclear factor κB (NF-κB) pathway in hemorrhagic shock (HS) rats. METHODS: HS was induced in male Sprague-Dawley rats by withdrawing blood to maintain a mean arterial pressure of 20 mm Hg to 25 mm Hg for 40 minutes. The rats were resuscitated by the reinfusion of the drawn blood, and a vehicle (HS), a low-dose of niacin (360 mg/kg, HS + LD-NA), or a high dose of niacin (1,080 mg/kg, HS + HD-NA) were administered orally. The survival of the subjects was observed for 72 hours, and a separate set of animals was killed at 6 hours after HS induction. We measured cytoplasmic phosphorylated inhibitor κB-α and inhibitor κB-α expressions, nuclear NF-κB p65 expression, NF-κB p65 DNA-binding activity, MEK partner 1 activity, tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-8, nicotinamide adenine dinucleotide (NAD+), reduced nicotinamide adenine dinucleotide phosphate, reduced glutathione, glutathione disulfide, malondialdehyde levels, and histologic damage in the lung tissue. We also measured TNF-α, IL-6, and IL-8 levels in the serum. RESULTS: The survival rates of the sham, HS, HS + LD-NA, and HS + HD-NA groups were 6 of 6 (100%), 0 of 9 (0%), 1 of 9 (11.1%), and 3 of 9 (33.3%), respectively. A high dose of niacin increased lung NAD+, nicotinamide adenine dinucleotide phosphate levels, and glutathione-glutathione disulfide ratios; decreased lung malondialdehyde levels; down-regulated the NF-κB pathway; suppressed TNF-α, IL-6, and IL-8 levels in the lung tissue and serum; and attenuated histologic lung damage. CONCLUSION: A high dose of niacin attenuated lung inflammation, suppressed proinflammatory cytokine release, reduced histologic lung damage, and improved survival after HS in rats. Its therapeutic benefits were associated with the down-regulation of the reactive oxygen species-dependent NF-κB pathway.