Vertebral fracture is associated with myocardial infarction in incident hemodialysis patients: a Korean nationwide population-based study.

Chronic kidney disease (CKD)-mineral and bone disorder suggests that fragile bone and vascular disorder might be connected closely in CKD patients. In this study, fracture event was significantly associated with myocardial infarction (MI) in end-stage renal disease patients on hemodialysis (HD), especially for vertebral fractures. INTRODUCTION: CKD-mineral and bone disorder is characterized by biochemical abnormalities, bone disorders, and vascular calcification. We aimed to verify the association between fracture and MI in CKD patients. METHODS: Records for incident CKD stage 3 to 5 patients and patients who initiated HD between July 2014 and June 2018 were retrieved from the Korean Health Insurance Review & Assessment Service Database. Fractures were defined using diagnostic codes and were classified into vertebral, femoral, and other site fractures. MI was defined using a combination of MI diagnostic codes and related procedure codes. Multiple logistic regressions and 1:1 propensity score matching analysis were conducted. RESULTS: A total of 38,935 patients (HD, 11,379; pre-dialysis CKD, 27,556) were included in this study. A total of 5,057 (13.0%) patients experienced fracture, and 1,431 (3.7%) patients had MI. Multiple logistic regression analysis showed that fracture was significantly associated with MI in the HD group (odds ratio (OR) 1.34, P = 0.024), but not in the pre-dialysis CKD group (OR 1.04, P = 0.701). After propensity score matching for age, gender, and diabetes mellitus between patients with and without fracture, fracture still significantly correlated with MI in HD patients (OR 1.47, P = 0.034) but not in patients with pre-dialysis CKD (OR 1.04, P = 0.751). Subgroup analysis by fracture site found that vertebral fracture was associated with MI in HD patients (OR 2.11, P = 0.024), but femoral or other site fractures were not. CONCLUSION: In HD patients, fracture was significantly associated with MI, especially for vertebral fractures patients.

Randomized, Open-Label, Phase IV, Korean Study of Kidney Transplant Patients Converting From Cyclosporine to Prolonged-Release Tacrolimus Plus Standard- or Reduced-Dose Corticosteroids.

BACKGROUND: This 24-week, multicenter, randomized, exploratory, comparative, open-label, phase-IV study assessed the safety and efficacy of prolonged-release tacrolimus (PR-T) with reduced-dose versus standard-dose corticosteroids in stable kidney transplant recipients in Korea after converting from cyclosporine-based therapy. METHODS: At baseline, patients were converted from cyclosporine-based to PR-T-based immunosuppression and randomized (1:1) to receive either corticosteroids maintained at prestudy dose (standard-dose group) or tapered from week 4 to 50% of the prestudy dose by week 12 (reduced-dose group). Patients were seen at baseline and weeks 1, 4, 12, and 24. The primary endpoint was change in estimated glomerular filtration rate (Modification-of-Diet-in-Renal-Disease-4) between baseline and week 24. Secondary endpoints included either acute rejection or patient-reported satisfaction with PR-T. Adverse events (AEs) were recorded. RESULTS: Overall, 150 patients were randomized into a reduced-dose group (n = 73) and a standard-dose group (n = 77). At week 24, mean ± standard deviation for corticosteroid dose was 2.5 ± 0.9 mg and 5.0 ± 1.3 mg, respectively. Mean change in estimated glomerular filtration rate from baseline to week 24 was +1.5 ± 9.1 mL/min/1.73 m2 (P = .1567) and +3.4 ± 10.6 mL/min/1.73 m2 (P = .0065), respectively, and not significantly different between groups. There were no acute rejection episodes. Most respondents (>70%) considered PR-T more convenient than cyclosporine. AE incidence was similar between groups. The most common AEs experienced by ≥3% of patients in either treatment group were gastrointestinal events (20.8% and 28.6% of patients receiving reduced- and standard-dose corticosteroids, respectively). Most AEs in both treatment groups were mild or moderate in severity. CONCLUSION: Renal function was maintained following conversion from cyclosporine to PR-T, irrespective of corticosteroid regimen; PR-T enables reduced corticosteroid dosage.

Direct bilirubin is associated with low-density lipoprotein subfractions and particle size in overweight and centrally obese women.

BACKGROUND AND AIMS: Bilirubin has antioxidant and anti-inflammatory properties; serum bilirubin levels have been known to be inversely associated with cardiovascular disease. However, the effects of different bilirubin subtypes on cardiometabolic traits are unknown. In this study, we aimed to determine whether direct bilirubin is more strongly correlated with small, dense low-density lipoprotein (sdLDL) compared to other bilirubin subtypes. We also investigated which LDL subfractions exhibited the highest correlation with direct bilirubin. METHODS AND RESULTS: A total of 288 overweight and centrally obese women were included in this study. The Pearson correlation and Steiger's Z test were used to compare the correlation coefficients between bilirubin subtypes and lipoproteins. Multiple linear regression analyses were used to evaluate the independent association between direct bilirubin and mean LDL particle size. Only direct bilirubin levels were significantly associated with the sdLDL subfraction and mean LDL particle size. Mean LDL particle size exhibited a significantly stronger correlation with direct bilirubin than sdLDL, percent sdLDL, and the sdLDL:large LDL ratio. Regression analysis showed that direct bilirubin was significantly associated with mean LDL particle size, according to both the stepwise method (ß = 11.445, P value = 0.002) and the enter method (ß = 11.655, P value = 0.002). CONCLUSIONS: Direct bilirubin is more strongly correlated with the sdLDL subfraction compared with total and indirect bilirubin, and is independently associated with mean LDL particle size in overweight and centrally obese women.

Police Officers' Knowledge and Attitudes Toward Brain Death and Organ Donation in Korea.

BACKGROUND: Administrative processing by the police may affect the process involved in organ donation in the event of an accidental brain injury. The purpose of this study was to evaluate the knowledge and attitude of police toward brain-dead donors and organ donation. METHODS: This was a descriptive research study using a 41-item questionnaire. As of July 19, 2017, 11 police stations in Seoul had collected questionnaires completed by 115 police officers. Data were analyzed using SAS (version 9.4) software. RESULTS: There were statistically significant differences in the scores on knowledge about brain death/donation according to religion (P = .022). Attitude was significantly positively correlated with the knowledge about brain-death organ donation (P = .029). CONCLUSION: It is necessary to understand and cooperate with the police when processing brain death organs from accidents. Education about organ donation can enhance the information and knowledge of the police and can also help to establish a positive attitude about organ donation.

Total serum bilirubin and 8-year incident type 2 diabetes mellitus: The Korean Genome and Epidemiology Study.

AIM: In this study, the impact of serum bilirubin on new-onset type 2 diabetes mellitus (T2DM) in Korean adults was investigated. METHODS: Data were obtained from the Korean Genome and Epidemiology Study (KoGES), a population-based prospective cohort study. The study enrolled 8650 adults (4015 men and 4635 women), aged 40 to 69 years, who underwent a mean follow-up of 8.4 years. The study population was divided into quartiles (Q) of serum bilirubin levels, with cut-off points at 0.46, 0.61 and 0.82mg/dL for men, and 0.35, 0.47 and 0.61mg/dL for women. T2DM was defined based on the following data: fasting blood glucose≥7.0mmol/L, HbA1c level≥6.5% or 2-h plasma glucose≥11.1mmol/L during a 75-g oral glucose tolerance test. RESULTS: Over the mean 8.4-year follow-up, 786 participants (9.1%) developed T2DM. Compared with Q1, the odds ratios (ORs) and 95% confidence intervals (CIs) for T2DM incidence were 0.52 (0.36-0.74) in men and 0.56 (0.38-0.83) in women aged ≥50 years, respectively, in the highest Q group after adjusting for possible confounding factors. These significant results persisted in those with impaired glucose tolerance and impaired fasting glucose. CONCLUSION: The results of this study reveal a protective role for serum total bilirubin on new-onset T2DM in Korean men and women. In addition, serum total bilirubin had favourable effects on new-onset T2DM in those with impaired glucose tolerance and impaired fasting glucose.

Elevated leukocyte count is associated with periodontitis in Korean adults: the 2012-2014 KNHANES.

OBJECTIVE: Both an elevated leukocyte count and periodontitis share well-recognized associations with cardiometabolic diseases. This cross-sectional study aimed to identify whether the leukocyte count is associated with periodontitis in a nationally representative Korean adult population. MATERIALS AND METHODS: Data from 9391 participants (3659 males and 5732 females) enrolled in 2012-2014 Korean National Health and Nutrition Examination Survey were analyzed. Leukocyte quartiles were categorized as follows: 3000 ≤ Q1 ≤ 4870, 4880 ≤ Q2 ≤5790, 5800 ≤ Q3 ≤ 6840, and 6850 ≤ Q4 ≤ 10000 cells/µl. Periodontitis was defined as scoring greater than or equal to 'code 3' in at least one site according to the WHO's Community Periodontal Index. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for periodontitis in each leukocyte count quartile were calculated using multiple logistic regression analyses. RESULTS: The prevalence of periodontitis was directly correlated with increasing leukocyte quartiles: 19%, 20.4%, 24.3%, and 30.3%. Compared with the lowest leukocyte quartile group, the OR (95% CI) for periodontitis of the highest leukocyte quartile was 1.558 (1.285-1.891) after controlling for confounding factors. CONCLUSION: An elevated leukocyte count was positively associated with the presence of periodontitis.

ROS1 Kinase Inhibitors for Molecular-Targeted Therapies.

ROS1 is a pivotal transmembrane receptor protein tyrosine kinase which regulates several cellular processes like apoptosis, survival, differentiation, proliferation, cell migration, and transformation. There is increasing evidence supporting that ROS1 plays an important role in different malignancies including glioblastoma, colorectal cancer, gastric adenocarcinoma, inflammatory myofibroblastic tumor, ovarian cancer, angiosarcoma, and non small cell lung cancer; thus, ROS1 has become a potential drug discovery target. ROS1 shares about 49% sequence homology with ALK primary structure; therefore, wide range of ALK kinase inhibitors have shown in vitro inhibitory activity against ROS1 kinase. After Crizotinib approval by FDA for the management of ALK-rearranged lung cancer, ROS1-positive tumors have been focused. Although significant advancements have been achieved in understanding ROS1 function and its signaling pathways plus recent discovery of small molecules modulating ROS1 protein, a vital need of medicinal chemistry efforts is still required to produce selective and potent ROS1 inhibitors as an important therapeutic strategy for different human malignancies. This review focuses on the current knowledge about different scaffolds targeting ROS1 rearrangements, methods to synthesis, and some biological data about the most potent compounds that have delivered various scaffold structures.

Comparison of the efficacy of tenofovir and entecavir for the treatment of nucleos(t) ide-naïve patients with chronic hepatitis B.

BACKGROUND: An important goal in the treatment of chronic hepatitis B virus (HBV) infection is to prevent hepatocellular carcinoma and liver cirrhosis by suppressing HBV replication. Tenofovir and entecavir are effective viral suppression compounds. However, comparative data is scant, especially in Korea. This study compared tenofovir and entecavir concerning efficiencies and side effects. MATERIALS AND METHODS: We retrospectively reviewed data of nucleos (t) ide-naïve patients with chronic HBV infection. Independent variables reflecting virological response were evaluated, and the decline in serum HBV DNA levels, and side effects between tenofovir-and entecavir-treated patients were compared at treatment week 12, 24, and 48. RESULTS: At the end of 48 weeks, there was no statistical difference in the induction of undetectable levels of HBV DNA between the entecavir (82.5%) and tenofovir (69.2%) groups. Entecavir was more effective in reducing serum HBV DNA levels at 24 weeks of treatment (serum HBV DNA decline of 5.53 and 4.95 log10 units for entecavir and tenofovir, respectively; P=0.044), but the rate of decline was similar at other weeks. There was no difference between the two groups in terms of side effects and discontinuance of treatment due to side effects. CONCLUSIONS: Tenofovir is not significantly different from entecavir in virologic response and tolerability in the treatment of chronic HBV.

Mixing-sequence-dependent nucleic acid complexation and gene transfer efficiency by polyethylenimine.

Polyplexes, complexed nucleic acids by cationic polymers, are the most common forms of nonviral gene delivery vectors. In contrast to a great deal of efforts in synthesizing novel cationic polymers and exploring their extracellular and intracellular delivery pathways, polyplex preparation methods of mixing nucleic acids and cationic polymers are often overlooked. In this study, the mixing sequence, that is adding nucleic acids to polymers or vice versa, was found to greatly affect complexation of both plasmid DNA and siRNA, polyplexes' size, and polyplexes' surface charge, which all collaboratively affected the transfection efficiency and cytotoxicity. Adding polyethylenimine (PEI), the most conventionally used standard in nonviral gene delivery, to plasmid DNA and siRNA resulted in larger polyplexes, higher gene expression and silencing, but higher cytotoxicity than polyplexes prepared in the reverse order. Based on the experimental results, the authors developed a model that gradual addition of cationic polymers (e.g., PEI) to nucleic acids (e.g., plasmid DNA and siRNA) incorporates more copies of nucleic acids in larger polyplexes in a smaller number, results in higher gene expression and silencing levels in transfected cells, and generates higher cytotoxicity by leaving more free polymers upon complete mixing than the other mixing sequence. The proposed model can be explored using a broad range of cationic polymers and nucleic acids, and provide insightful information about how to prepare polyplexed nonviral vectors for efficient and safe gene delivery.

A lazy learning-based QSAR classification study for screening potential histone deacetylase 8 (HDAC8) inhibitors.

Histone deacetylases 8 (HDAC8) is an enzyme repressing the transcription of various genes including tumour suppressor gene and has already become a target of human cancer treatment. In an effort to facilitate the discovery of HDAC8 inhibitors, two quantitative structure-activity relationship (QSAR) classification models were developed using K nearest neighbours (KNN) and neighbourhood classifier (NEC). Molecular descriptors were calculated for the data set and database compounds using ADRIANA.Code of Molecular Networks. Principal components analysis (PCA) was used to select the descriptors. The developed models were validated by leave-one-out cross validation (LOO CV). The performances of the developed models were evaluated with an external test set. Highly predictive models were used for database virtual screening. Furthermore, hit compounds were subsequently subject to molecular docking. Five hits were obtained based on consensus scoring function and binding affinity as potential HDAC8 inhibitors. Finally, HDAC8 structures in complex with five hits were also subjected to 5 ns molecular dynamics (MD) simulations to evaluate the complex structure stability. To the best of our knowledge, the NEC classification model used in this study is the first application of NEC to virtual screening for drug discovery.