TGF-ß1 polymorphism increases the risk of bleeding complications in patients on oral anticoagulant after cardiac valve replacement.

Although an elevated INR is highly associated with an increased risk of warfarin-associated bleeding, it has been reported that some patients also experience bleeding complications at therapeutic INRs. TGF-ß1 polymorphisms has been reported to cause vascular malformations, resulting in bleeding complications, but there are few published genetic studies regarding bleeding complications in patients on warfarin therapy. This study aimed to determine if there is an association between transforming growth factor beta-1 (TGF-ß1) polymorphisms and bleeding complications in patients who maintain international normalized ratios (INRs) of 2.0-3.0 with warfarin therapy after cardiac valve replacement. Eleven single nucleotide polymorphis (SNPs) of TGF-ß1 (rs1800469, rs2241718, rs4803455, rs2241717, rs2241716, rs2241715, rs2241714, rs11083616, rs2317130, rs747857, and rs1982073) were analyzed. Univariate and multivariable analyses were conducted to evaluate the associations between genetic polymorphisms and bleeding risk. Attributable risk and the number needed to genotype (NNG) were calculated to identify the potential clinical value of genotyping. A discrimination of model was assessed via an analysis of the area under the receiver operating curve (AUROC). To test the model's goodness of fit, a Hosmer-Lemeshow test was performed. Of 142 patients, 21 experienced bleeding complications. Among analyzed single nucleotide polymorphis (SNPs) of TGF-ß1 (rs1800469, rs2241718, rs4803455, rs2241717, rs2241716, rs2241715, rs2241714, rs11083616, rs2317130, rs747857, and rs1982073), AA genotype carriers in rs2241718 had about 5.5 times more bleeding complications than those with the G allele after adjusting for other confounders. The attributable risk and NNG for rs2241718 were 81.9% and 57.8, respectively. The presence of atrial fibrillation and myocardial infarction increased bleeding complications 3.9- and 9.8-fold, compared with those without atrial fibrillation and myocardial infarction, respectively. Bleeding complications during warfarin therapy in patients with mechanical heart valves were associated with TGF-ß1 polymorphisms as well as atrial fibrillation and myocardial infarction.

Effects of KCNMB2 gene polymorphisms on ritodrine therapy outcomes in women with preterm labor.

OBJECTIVE: The present prospective follow-up study aimed to evaluate the effects of KCNMB2 gene polymorphisms on ritodrine efficacy and adverse drug events (ADEs) in patients with preterm labor. METHODS: A total of 163 preterm labor patients were included in this single-center study. Nine single nucleotide polymorphisms (SNPs) in the KCNMB2 gene (rs10936979, rs7624046, rs7429015, rs7625907, rs6443559, rs9839376, rs9637454, rs11918114, and rs1382045) were assessed. The primary endpoint was time to delivery, and the secondary endpoint was ritodrine-induced ADEs. RESULTS: Patients with variant homozygotes of two SNPs (rs7624046 and rs9839376), which were in linkage disequilibrium, showed 2.06 [95% confidence interval (CI), 1.14-3.73] and 2.68 (95% CI, 1.16-6.20) times the hazard of time to delivery compared to wild-type allele carriers, respectively. Among demographic characteristics, gestational age at start of drug therapy and modified Bishop score were significant factors for time to delivery. Regarding safety outcomes, patients with variant homozygotes of rs7625907 had fewer ADEs compared to those with other genotypes (odds ratio, 0.32; 95% CI, 0.13-0.83). CONCLUSION: This pharmacogenomic study suggests that ritodrine efficacy and ADEs are associated with KCNMB2 gene polymorphisms in patients with preterm labor.

Population Pharmacokinetics of Sulindac and Genetic Polymorphisms of FMO3 and AOX1 in Women with Preterm Labor.

PURPOSE: This prospective study aimed to evaluate the effects of genetic polymorphisms in sulindac-related metabolizing enzyme genes including FMO3 and AOX1 on the population pharmacokinetics of sulindac in 58 pregnant women with preterm labor. METHODS: Plasma samples were collected at 1.5, 4, and 10 h after first oral administration of sulindac. Plasma concentrations of sulindac and its active metabolite (sulindac sulfide) were determined, and pharmacokinetic analysis was performed with NONMEM 7.3. RESULTS: The mean maternal and gestational ages at the time of dosing were 32.5 ± 4.4 (range, 20-41) years and 27.4 ± 4.4 (range, 16.4-33.4) weeks, respectively. In the population pharmacokinetic analysis, one depot compartment model of sulindac with absorption lag time best described the data. The metabolism of sulindac and sulindac sulfide was described using Michaelis-Menten kinetics. In stepwise modeling, gestational age impacted volume of distribution (Vc), and FMO3 rs2266782 was shown by the Michaelis constant to affect conversion of sulindac sulfide to sulindac (KM32); these were retained in the final model. CONCLUSIONS: Genetic polymorphisms of FMO3 and AOX1 could affect the pharmacokinetics of sulindac in women who undergo preterm labor. The results of this study could help clinicians develop individualized treatment plans for administering sulindac.

Association between HNF4A mutations and bleeding complications in patients with stable international normalized ratio.

OBJECTIVES: This study aimed to determine the association between hepatocyte nuclear factor 4 alpha (HNF4A) polymorphisms and bleeding complications in patients on warfarin with international normalized ratios between 2.0 and 3.0 after cardiac valve replacement. METHODS: Nineteen single nucleotide polymorphisms of HNF4A in addition to VKORC1 rs9934438 and CYP2C9 rs1057910 were analyzed. Univariate and multivariate analyses were conducted to evaluate associations between genetic polymorphisms and bleeding risk. Attributable risk and number needed to genotype (NNG) were calculated to assess clinical value of genotyping. RESULTS: Of 142 patients, 21 experienced bleeding complications. Multivariate logistic regression analysis was conducted using factors with P <0.1 in univariate analysis. Multivariate analysis showed that patients with the CC genotype of rs6130615 had an 8.4-fold increased risk of bleeding, compared with patients with the T allele. Attributable risk and NNG were 88.1% and 32.2, respectively. Patients with the TT genotype of rs3212191 had a 3.8-fold increased risk of bleeding, compared with C allele carriers, while patients with variant-type homozygotes for rs1884613 showed an 8.7-fold higher bleeding complication than C allele carriers. The attributable risk/NNG of rs3212191 and rs1884613 were 73.4%/17.6 and 88.5%/22.8, respectively. Among comorbidities, atrial fibrillation was the only significant risk factor for bleeding complications. CONCLUSION: Bleeding complications during warfarin therapy in patients with mechanical heart valves were associated with HNF4A polymorphisms and atrial fibrillation.

Effects of PDE4 gene polymorphisms on efficacy and adverse drug events of ritodrine therapy in preterm labor patients: a prospective observational study.

PURPOSE: Phosphodiesterase (PDE) terminates the signaling pathway of myometrial relaxation by degradating cAMP to the inactive 5'-AMP. The PDE4 family is one of the most predominant PDE families that display high affinity to cAMP. The objective of this study was to evaluate the effects of PDE4 gene polymorphisms on tocolytic effects and adverse drug events (ADEs) of ritodrine therapy in patients with preterm labor. METHODS: A total of 170 preterm labor patients were included in this study. To elucidate the effects of genetic polymorphisms on the inter-individual variability of ritodrine efficacy and ADEs, 8 single nucleotide polymorphisms (SNPs) were genotyped: PDE4D (rs1544791, rs983280, rs1504982, rs10940648, rs829259) and PDE4B2 (rs598961, rs2180335, and rs17128809). Additionally, rs1042719 of the ADRB2 gene was included for multivariate analysis. The primary endpoint of this prospective study was the time to delivery (hr). The secondary endpoint was ritodrine-induced ADEs. RESULTS: The mutant-type homozygote carriers of PDE4B2 rs598961 polymorphism showed shorter median time to delivery than those with other genotypes (adjusted hazard ratio 1.6, 95% confidence interval 1.0 to 2.4, P = 0.035). On the other hand, patients with wild-type homozygotes of PDE4B2 rs17128809 showed 2.6~2.9 times higher ADEs compared to those with other genotypes. Among demographic characteristics, gestational age at start of drug therapy and modified Bishop score were significant factors for time to delivery, whereas height, weight, and BSA were significant factors for ritodrine-induced ADEs after adjusting other factors. CONCLUSIONS: This pharmacogenomic study suggested that PDE4 genetic polymorphisms impact individual susceptibility to ß2-adrenergic receptor targeted therapy in patients with preterm labor.

Association between anxiety and aggression in adolescents: a cross-sectional study.

BACKGROUND: The purpose of this study was to investigate the relationship between anxiety proneness and aggressive behavior in adolescents. METHODS: A quantitative, large scale cross-sectional study was conducted in Korea. The survey questionnaire included general health behavior and scales for assessing anxiety (Revised Children's Manifest Anxiety Scale; RCMAS) and aggressive behavior (The Aggression Questionnaire; AQ) in adolescents. RESULTS: A total of 2432 students participated in the survey, and 1933 individuals completed the questionnaire, indicating a response rate of 79.5%. Based on RCMAS, 163 (8.4%) subjects were classified as the anxiety group. Aggressive behavior was significantly associated with higher anxiety scores. In particular, among four subdomains of aggression, anger and hostility had a stronger relationship with anxiety than did physical and verbal aggression. Multivariate analysis demonstrated that anxiety was independently associated with gender, age, headache, constipation, asthma, and aggression score. Adolescents with total aggression scores of 69 or higher showed a 9-fold (AOR = 9.00, CI = 6.33-13.51) higher risk of anxiety compared to those with under 69. CONCLUSION: Aggression and anxiety are important aspects of mental health in adolescents. Our results demonstrated that higher risk of anxiety was associated with total aggression scores. In particular, indirect aggression (i.e. anger and hostility) was more closely associated with anxiety than direct aggression.

Association between MKRN3 and LIN28B polymorphisms and precocious puberty.

BACKGROUND: The present study aimed to investigate the association between MKRN3 and LIN28B gene polymorphisms and precocious puberty in Korean boys and girls. RESULTS: Children 7 to 9 years of age in 2011 to 2012 who were part of the Ewha Birth & Growth Cohort Study were recruited for this study. A total of 103 girls and 70 boys were included in the analyses. Seven girls and 26 boys were identified to have precocious puberty. Among four single nucleotide polymorphisms (SNPs) of MKRN3 and two SNPs of LIN28B examined, three SNPs (rs2239669, rs6576457, and rs12441827) showed significant associations with precocious puberty in additive models in boys but no significance was found in any SNPs in girls. From the logistic regression analysis, boys with TT alleles in rs12441827 had about a four-times greater risk for precocious puberty when compared to C allele carriers (OR = 3.95, 95% CI = 1.27-12.32 in model 1). eQTL analysis revealed that SNPs of statistical significance from our study did not show the variation in expression profiles nor found in the database. CONCLUSIONS: This study supports the impact of MKRN3 SNP rs12441827 on precocious puberty in Korean boys. The results add a further aspect to genetic association in precocious puberty along with complex interactions of environmental, nutritional and socioeconomic factors.

Smartphone addiction risk and daytime sleepiness in Korean adolescents.

AIM: Smartphone overuse can cause not only mobility problems in the wrists, fingers and neck but also interference with sleep habits. However, research on smartphone addiction and sleep disturbances is scarce. Therefore, we aimed to investigate daytime sleepiness in association with smartphone addiction risk in Korean adolescents. METHODS: A cross-sectional survey method was used in this study. The Pediatric Daytime Sleepiness Scale was used to assess daytime sleepiness, and the Korean Smartphone Addiction Proneness Scale index was used to evaluate the degree of risk for smartphone addiction. RESULTS: The analyses were performed in 1796 adolescents using smartphones, including 820 boys and 976 girls. The at-risk smartphone users made up 15.1% of boys and 23.9% of girls. Our multivariate analyses demonstrated that students who were female, consumed alcohol, had lower academic performance, did not feel refreshed in the morning and initiated sleep after 12 am were at a significantly higher risk of smartphone addiction. The at-risk smartphone user group was independently associated with the upper quartile Pediatric Daytime Sleepiness Scale score in students with the following factors: Female gender, alcohol consumption, poor self-perceived health level, initiating sleep after 12 am, longer time taken to fall asleep and duration of night sleep less than 6 h. CONCLUSIONS: The quality of sleep in adolescence affects growth, emotional stability and learning skills. Therefore, the management of smartphone addiction seems to be essential for proper sleeping habits. There is a critical need to develop a means of preventing smartphone addiction on a social level.

Association of pre-operative medication use with post-surgery mortality and morbidity in oncology patients receiving comprehensive geriatric assessment.

BACKGROUND: Comprehensive geriatric assessment (CGA) has become a predictor for elderly cancer patients in post-surgical complications, including post-discharge institutionalization and mortality. AIMS: To determine whether pre-operative medication use is associated with post-operative morbidity and mortality in oncology patients receiving CGA. METHODS: Patients aged 65 years or older who were scheduled for cancer surgery and presented for CGA were included in the present study. Baseline characteristics of patients were collected from electrical medical records, and pre-operative medication review was performed. The primary outcome was death within 30 days after surgery and post-discharge institutionalization. RESULTS: A total of 475 cancer patients were included. Among them, three patients died within 30 days after surgery and 14 patients were discharged to another institution. All patients who died within 30 days after surgery had polypharmacy with marginal significance (P = 0.087). Multivariate analysis models were constructed using significant factors for post-surgery institutionalization from univariate analysis: Model I (polypharmacy and transfusion), Model II (polypharmacy and infection), and Model III (polypharmacy, transfusion, and infection). Infection was the most significant factor. Its adjusted odds ratio was as large as 11.1 and attributable risk was almost 91%. In pre-surgery medication use, only polypharmacy showed significant association with post-discharge institutionalization. Attributable risk of polypharmacy was around 75%. CONCLUSIONS: It is possible that pre-operative medication use has impact on death and post-discharge institutionalization in geriatric oncology patients, further highlighting the importance of medication optimization for elderly patients with cancer surgery.

Association between ß2-adrenergic receptor gene polymorphisms and adverse events of ritodrine in the treatment of preterm labor: a prospective observational study.

BACKGROUND: Ritodrine, a tocolytic ß2-agonist, has been used extensively in Europe and Asia despite its safety concerns. This study was designed to identify associations between ß2-adrenergic receptor (ADRB2) polymorphisms and adverse drug events (ADEs) in patients with preterm labor treated with ritodrine. RESULTS: This follow-up study was prospectively conducted at Ewha Womans University Mokdong Hospital in Korea. Five single nucleotide polymorphisms (SNPs) of the ADRB2 gene (rs1042713, rs1042714, rs1042717, rs1042718, and rs1042719) were analyzed in 186 pregnant women with preterm labor. Patients with the AA genotype of rs1042717 had significantly lower incidence of ADEs compared to those with the G allele (p = 0.009). In multivariate analysis, one of the predictors of ADEs was the maximum infusion rate of ritodrine (AOR 4.47, 95% CI 1.31-15.25). Rs1042719 was also a significant factor for ritodrine-induced ADEs. The CC genotype carriers had 78% decreased risk of ADEs compared to those with other genotypes. CONCLUSIONS: This study demonstrates that ADEs induced by ritodrine are associated with ADRB2 gene polymorphisms, as well as the infusion rate of ritodrine in pregnant women with preterm labor.

Association between CACNA1C gene polymorphisms and ritodrine-induced adverse events in preterm labor patients.

PURPOSE: As a tocolytic agent, ritodrine has been used in European and Asian countries but has lost popularity due to safety concerns. This study aimed to investigate the relationship between adverse drug events caused by ritodrine and the CACNA1C polymorphisms in preterm labor patients. METHODS: Data were collected from medical records including maternal age, gestational age, body mass index, dilation score, effacement score, modified Bishop score, maximum infusion rate, and adverse drug events. Five single-nucleotide polymorphisms of the CACNA1C gene (rs10774053, rs215994, rs215976, rs2239128, and rs2041135) were analyzed. RESULTS: One hundred eighty-six patients were included, 33 of whom had adverse drug events. A allele carriers of rs10774053 showed about 0.293-fold lower adverse drug events than GG genotype carriers (p = 0.012, absolute risk reduction = 16.5%) after adjusting for other confounding variables; the number needed to genotype for preventing one patient with GG genotype from suffering higher incidence of adverse drug events was calculated to be 14.6. Increase in maximum infusion rate of 1 mL/h was associated with a 1.03-fold (95% CI 1.01~1.06, p = 0.005) increased risk of adverse drug events. None of the patients with a CC genotype of rs215994 had adverse drug events, whereas 22.1% of the T allele carriers had adverse drug events. CONCLUSION: This study showed that CACNA1C gene polymorphisms could alter the probability of adverse drug event risk when ritodrine is used in preterm labor.

Association of pre-operative medication use with post-operative delirium in surgical oncology patients receiving comprehensive geriatric assessment.

BACKGROUND: Older patients undergoing surgery tend to have a higher frequency of delirium. Delirium is strongly associated with poor surgical outcomes. This study evaluated the association between pre-operative medication use and post-operative delirium (POD) in surgical oncology patients receiving comprehensive geriatric assessment (CGA). METHODS: A total of 475 patients who were scheduled for cancer surgery and received CGA from January 2014 to June 2015 were included. Pre-operative medication review through CGA was conducted on polypharmacy (≥5 medications), delirium-inducing medications (DIMs), fall-inducing medications (FIMs), and potentially inappropriate medications (PIMs). POD was confirmed by psychiatric consultation, and DSM-V criteria were used for diagnosing delirium. The model fit of the prediction model was assessed by computing the Hosmer-Lemeshow goodness-of-fit test. Effect size was measured using the Nagelkerke R(2). Discrimination of the model was assessed by an analysis of the area under receiver operating curve (AUROC). RESULTS: Two models were constructed for multivariate analysis based on univariate analysis; model I included dementia and DIM in addition to age and sex, and model II included PIM instead of DIM of model I. Every one year increase of age increased the risk of POD by about 1.1-fold. DIM was a significant factor for POD after adjusting for confounders (AOR 12.78, 95 % CI 2.83-57.74). PIM was also a significant factor for POD (AOR 5.53, 95 % CI 2.03-15.05). The Hosmer-Lemeshow test results revealed good fits for both models (χ(2) = 3.842, p = 0.871 for model I and χ(2) = 8.130, p = 0.421 for model II). The Nagelkerke R(2) effect size and AUROC for model I was 0.215 and 0.833, respectively. Model II had the Nagelkerke R(2)effect size of 0.174 and AUROC of 0.819. CONCLUSIONS: These results suggest that pharmacists' comprehensive review for pre-operative medication use is critical for the post-operative outcomes like delirium in older patients.

Effects of NAD(P)H quinone oxidoreductase 1 polymorphisms on stable warfarin doses in Korean patients with mechanical cardiac valves.

PURPOSE: NAD(P)H dehydrogenase, encoded by NAD(P)H quinone oxidoreductase 1 (NQO1), is an enzyme that catalyzes the reduction of quinones, including vitamin K. Given its potential role in vitamin K metabolism, this study aimed to investigate the effects of NQO1 polymorphisms on stable warfarin doses. METHODS: We tested a possible effect of gene polymorphisms on variability in warfarin response using 206 Korean patients with mechanical cardiac valves. Single nucleotide polymorphisms (SNPs) of NQO1 with a minor allele frequency of at least 15% were included. Also, genotypes of vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 (CYP) 2C9, CYP4F2, gamma-glutamyl carboxylase (GGCX), and GATA4 were determined. RESULTS: NQO1 rs1800566 (C>T) and rs10517 (C>T) were significantly associated with stable warfarin doses. Variant homozygote carriers required lower stable warfarin doses than those with wild-type C allele in rs1800566 (4.85 ± 1.61 vs. 5.61 ± 1.94 mg; p = 0.033), whereas patients with wild homozygote required lower doses than those with T allele in rs10517 (5.11 ± 1.73 vs. 5.75 ± 1.98 mg; p = 0.017). Similar results were obtained from stratified analysis using VKORC1 variant homozygote carriers in both SNPs. Multivariate analysis showed that rs10517 (C>T) increased contribution of gene variations to the overall warfarin dose variability from 42.5 to 43.8%. CONCLUSION: Our results demonstrate that NQO1 gene polymorphisms influence stable warfarin doses in Korean patients.

Impacts of regular physical activity on hospitalisation in chronic obstructive pulmonary disease: a nationwide population-based study.

INTRODUCTION: Studies that comprehensively evaluate the association between physical activity (PA) levels, particularly by quantifying PA intensity, and healthcare use requiring emergency department (ED) visit or hospitalisation in patients with chronic obstructive pulmonary disease (COPD) are limited in Korea. METHODS: The risk of all-cause and respiratory ED visit or hospitalisation according to the presence or absence of COPD and the level of PA was evaluated in a retrospective nationwide cohort comprising 3308 subjects with COPD (COPD cohort) and 293 358 subjects without COPD (non-COPD cohort) from 2009 to 2017. RESULTS: The COPD group exhibited a higher relative risk of all-cause and respiratory ED visit or hospitalisation across all levels of PA compared with the highly active control group (≥1500 metabolic equivalents (METs)-min/week). Specifically, the highest risk was observed in the sedentary group (adjusted HR (aHR) (95% CI) = 1.70 (1.59 to 1.81) for all-cause ED visit or hospitalisation, 5.45 (4.86 to 6.12) for respiratory ED visit or hospitalisation). A 500 MET-min/week increase in PA was associated with reductions in all-cause and respiratory ED visit or hospitalisation in the COPD cohort (aHR (95% CI) = 0.92 (0.88 to 0.96) for all-cause, 0.87 (0.82 to 0.93) for respiratory cause). CONCLUSIONS: Compared with the presumed healthiest cohort, the control group with PA>1500 METs-min/week, the COPD group with reduced PA has a higher risk of ED visit or hospitalisation.

Nutrition Therapy by Nutrition Support Team: A Comparison of Multi-Chamber Bag and Customized Parenteral Nutrition in Hospitalized Patients.

This study aimed to investigate the activity of a nutrition support team (NST) and the trends of multi-chamber bag (MCB) and customized parenteral nutrition (PN) with NST consultations in South Korea. Data were obtained from the National Inpatient Sample Cohort between 2015 and 2020. Three datasets were constructed for NST consultation, MCB-PN product prescriptions, and aseptic preparation of total PN. The intersections of the NST consultation and each PN dataset were compiled into MCB-PN with NST or customized PN with a NST sub-dataset, respectively. Using personal identifiers, the patients' characteristics were evaluated in the NST cohort. A total of 91,384 reimbursements and 70,665 patients were included. The NST activity had increased by more than 50% over 6 years. Approximately 70% and 11%, respectively, of the NST cohort were classified into two subgroups: MCB-PN with NST (M-NST) and customized PN with NST (C-NST). M-NST had many elderly patients with cancer and showed a higher in-hospital mortality than C-NST (12.6% vs. 9.5%). C-NST included a larger number of patients under the age of 5 years, and the hospitalization period was more extended than M-NST (26.2 vs. 21.2 days). The present study showed that NST activities and the proportion of PN with NST consultation are gradually increasing in South Korea.

Interactive Associations between PPARγ and PPARGC1A and Bisphosphonate-Related Osteonecrosis of the Jaw in Patients with Osteoporosis.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but severe adverse effect that can occur as a result of bisphosphonate treatment. This study aimed to examine the relationship between PPARγ and PPARGC1A polymorphisms and the BRONJ development in female osteoporosis patients undergoing bisphosphonate treatment. We prospectively conducted this nested case-control study at the Ewha Womans University Mokdong Hospital between 2014 and 2018. We assessed five single-nucleotide polymorphisms (SNPs) of PPARγ and six SNPs of PPARGC1A and performed a multivariable logistic regression analysis to determine the independent risk factors for developing BRONJ. There were a total of 123 patients included in this study and 56 patients (45.5%) developed BRONJ. In the univariate analysis, PPARGC1A rs2946385 and rs10020457 polymorphisms were significantly associated with BRONJ (p = 0.034, p = 0.020, respectively), although the results were not statistically significant in the multivariable analysis. Patients with the combined genotypes of GG in both PPARγ rs1151999 and PPARGC1A rs2946385 showed a 3.03-fold higher risk of BRONJ compared to individuals with other genotype combinations after adjusting for confounders (95% confidence interval (CI): 1.01-9.11). Old age (≥70 years) and duration of bisphosphonate use (≥60 months) increased the risk of BRONJ. The area under the receiver operating characteristic curve for the predicted probability was 0.78 (95% CI: 0.69-0.87, p < 0.001), demonstrating a satisfactory level of discriminatory power. Our study elucidated that PPARγ and PPARGC1A polymorphisms were interactively associated with BRONJ development. These results have potential implications for tailoring personalized treatments for females undergoing bisphosphonate therapy for osteoporosis.

Prediction of medication-related osteonecrosis of the jaws using machine learning methods from estrogen receptor 1 polymorphisms and clinical information.

Objective: The purpose of this study was to evaluate the effect of estrogen receptor 1 (ESR1) polymorphisms on the development of medication-related osteonecrosis of the jaws (MRONJ) in women with osteoporosis. Methods: A total of 125 patients taking bisphosphonates was evaluated the relationship between MRONJ occurrence and single nucleotide polymorphisms (SNPs) of ESR1. Clinical information was collected, including current age, treatment duration, and comorbidity. Univariate and Multivariable regression analyzes were performed to evaluate the independent predictive factors for MRONJ occurrence. Predictive models were constructed using machine learning methods such as Lasso regression, Random forest (RF), and Support vector machine (SVM). The area under the receiver-operating curve (AUROC) was used to evaluate the performance of a binary classifier. Result: Two SNPs of ESR1 (rs4870056 and rs78177662) were significantly associated with MRONJ development. Patients with variant allele (A) of rs4870056 showed 2.45 times (95% CI, 1.03-5.87) the odds of MRONJ occurrence compared to those with wild-type homozygote (GG) after adjusting covariates. Additionally, carriers with variant allele (T) of rs78177662 had higher odds than those with wild-type homozygote (CC) (adjusted odds ratio (aOR), 2.64, 95% CI, 1.00-6.94). Among demographic variables, age ≥ 72 years (aOR, 3.98, 95% CI, 1.60-9.87) and bisphosphonate exposure ≥48 months (aOR, 3.16, 95% CI, 1.26-7.93) were also significant risk factors for MRONJ occurrence. AUROC values of machine learning methods ranged between 0.756-0.806 in the study. Conclusion: Our study showed that the MRONJ occurrence was associated with ESR1 polymorphisms in osteoporotic women.

Effects of SLCO1B1 and SLCO1B3 Genetic Polymorphisms on Valsartan Pharmacokinetics in Healthy Korean Volunteers.

Purpose: This study aimed to examine OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) on the pharmacokinetics of valsartan. Twenty-five subjects were genotyped for 16 single-nucleotide polymorphisms of the SLCO1B1 and SLCO1B3 genes. Methods: After a single dose of 160 mg of valsartan was orally administered to healthy male volunteers, drug concentrations were assayed up to 48 h. The 25 subjects were genotyped for 16 single-nucleotide polymorphisms (SNPs) of the SLCO1B1 and SLCO1B3 genes. Subjects were classified into groups according to their SLCO1B1*1B haplotype; 23 subjects were carriers of SLCO1B1*1B and two subjects were included in the reference group with SLCO1B1*1A/*1A. Alternations of the splicing factor-binding site pattern caused by the given mutation were evaluated with the Human Splicing Finder (HSF) 3.1. Results: The subjects who carried SLCO1B1*1B showed a 2.3-fold higher clearance than those without the *1B haplotype. Mean Cmax and AUCinf were reduced by 45% and 54%, respectively, in the SLCO1B1*1B genotype group compared to the reference group with the *1A/*1A genotype (p < 0.01). The carriers of the rs4149153 T allele of SLCO1B3 had a 27% lower mean Cmax and a 1.5-fold higher Vd compared to homozygotic CC carriers (p < 0.05). In a combined analysis of SLCO1B1 and SLCO1B3, subjects not carrying SLCO1B1 *1B and carrying SLCO1B3 rs4149153 T allele showed a 1.6-fold higher clearance than those with the other genotypes, whereas mean Cmax and AUClast were reduced by 35% and 42%, respectively (p < 0.05), in the subjects. HSF 3.1 analysis showed that rs4149153 could cause alterations of the acceptor splice site (TAAATACTAAAGAC to TAAATATTAAAGAC) with scoring change (from 72.57 to 71.92, difference = -0.9). Conclusion: It was found that plasma exposure to valsartan is significantly decreased in SLCO1B1*1B carriers and carriers of the rs4149153 T allele of SLCO1B3, possibly as a result of increased hepatic uptake.

Comparative associations between anticholinergic burden and emergency department visits for anticholinergic adverse events in older Korean adults: a nested case-control study using national claims data for validation of a novel country-specific scale.

BACKGROUND: Considering the limited generalizability of previous anticholinergic burden scales, the Korean Anticholinergic Burden Scale (KABS) as a scale specific to the Korean population was developed. We aimed to validate the KABS by detecting the associations between high anticholinergic burden, measured with the KABS, and emergency department (ED) visits compared to the pre-existing validated scales in older Korean adults. METHODS: A nested case-control study was conducted using national claims data. The cases included the first anticholinergic ED visits between July 1 and December 31, 2016. Anticholinergic ED visits were defined as ED visits with a primary diagnosis of constipation, delirium, dizziness, fall, fracture, or urinary retention. Propensity score-matched controls were identified. Average daily AB scores during 30 days before the index date were measured. Multivariate logistic regression analyses were performed. RESULTS: In total, 461,034 were included. The highest proportion of those with high AB was identified with KABS (5.0%). Compared with those who had a KABS score of 0, older adults with a score ≥ 3 were at higher risk for overall anticholinergic ED visits (aOR, 1.62, 95% CI, 1.53-1.72), as well as visits for falls/fractures (aOR: 1.54, 95% CI: 1.40-1.69), dizziness (aOR: 1.44, 95% CI: 1.30-1.59), delirium (aOR: 2.96, 95% CI: 2.28-3.83), constipation (aOR: 1.84, 95% CI: 1.68-2.02), and urinary retention (aOR: 2.13, 95% CI: 1.79-2.55). High AB by KABS showed a stronger association with overall anticholinergic ED visits and visits due to delirium and urinary retention than those by other scales. CONCLUSIONS: In conclusion, KABS is superior to pre-existing scales in identifying patients with high AB and predicting high AB-related ED visits in older Korean adults.

Association between attention deficit hyperactivity disorder and aggression subscales in adolescents.

INTRODUCTION: The aim of this study is to identify the association between Attention Deficit Hyperactivity Disorder (ADHD) proneness and aggressive propensity in adolescents. METHODS: A quantitative, large-scale, cross-sectional study was performed from April to May 2016 in Korea. The survey questionnaire included overall health behaviors, as well as scales for assessing ADHD proneness (revised short form of the Conners-Wells Adolescent Self-Report Scale; CASS[S]) and aggressive behavior (Buss-Perry Aggression Questionnaire; BPAQ) in adolescents. Area under the receiver operator characteristic (AUROC) curves was constructed to determine the cut-off value of total aggression score for discriminating ADHD proneness. RESULTS: A total of 2,432 students participated in the survey, and 1,872 of them completed the questionnaire, indicating a response rate of 77.0%. Based on CASS(S), 33 (1.8%) subjects were classified as the ADHD group. AUROC curve analysis showed that a score of 68.5 points had higher sensitivity (83.3%) and specificity (69.4%) to discriminate ADHD proneness. ADHD proneness was significantly associated with higher aggression subdomain scores (physical, verbal, anger, and hostility). Especially, anger and hostility had a stronger relationship with ADHD proneness than did physical and verbal aggression. A multivariable analysis demonstrated that ADHD proneness was significantly related to body mass index in the top 10% of the study population, alcohol consumption, gastrointestinal trouble, daytime sleepiness, and total aggression score of 68.5 points or higher. Adolescents who had total aggression scores of 68.5 points or higher showed a 9.8-fold (95% confidence interval [CI] 3.3-28.8) higher risk of ADHD compared with those who had scores less than 68.5 points. CONCLUSIONS: Our results demonstrated that ADHD proneness was significantly associated with aggression propensity. In particular, anger and hostility were more closely associated with ADHD proneness than were other aggression subdomains.