Sleep-related adverse events of smoking cessation drugs: A network meta-analysis of randomized controlled trials.

Smoking cessation medications have the potential to affect the functioning of the nervous system, leading to sleep disturbances. Our study aimed to compare the sleep-related side effects (such as insomnia, abnormal dreams, nightmares, and somnolence) induced by different smoking cessation medications in non-psychiatric smokers. We conducted a thorough search of five electronic databases (Cochrane, EMBASE, PubMed, PsycInfo, and Web of Science) for randomized controlled trials. This study was registered with the PROSPERO (registration number CRD42022347976). A total of 79 full-text articles, encompassing 36,731 participants, were included in our analysis. Individuals using bupropion, bupropion in combination with a nicotinic acetylcholine receptor agonist (NRA), and bupropion in conjunction with nicotine replacement therapy (NRT) exhibited a higher likelihood of experiencing insomnia compared to those using NRT alone. Bupropion plus NRA had the highest ranking on the surface under the cumulative ranking curve (SUCRA) for insomnia risk, while placebo had the lowest ranking. Additionally, NRA plus NRT ranked first for abnormal dream outcomes, NRA alone for nightmares, and nortriptyline for somnolence, based on the SUCRA results. Healthcare providers should exercise caution when prescribing smoking cessation drugs, particularly in consideration of their potential sleep-related side effects.

Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants.

Introduction: Bleeding is one of the most undesirable complications of direct oral anticoagulants (DOACs). While the ryanodine receptor (RYR2) has been related to cardiac diseases, research on bleeding complications is lacking. This study aimed to elucidate the association between RYR2 and bleeding risk to develop the risk scoring system in patients treated with DOACs. Methods: This study was a retrospective analysis of prospectively collected samples. We selected ten SNPs within the RYR2 gene, and two models were constructed (Model I: demographic factors only, Model II: demographic and genetic factors) in multivariable analysis. Independent risk factors for bleeding were used to develop a risk scoring system. Results: A total of 447 patients were included, and 49 experienced either major bleeding or clinically relevant non-major bleeding. In Model I, patients using rivaroxaban and experiencing anemia exhibited an increased bleeding risk after adjusting for covariates. Upon incorporating genetic factors into Model I, a significant association with bleeding was also observed in cases of overdosing on DOACs and in patients with a creatinine clearance (CrCl) < 30 mL/min, in addition to rivaroxaban and anemia (Model II). Among genetic factors, RYR2 rs12594 GG, rs17682073 AA, rs3766871 GG, and rs6678625 T alleles were associated with bleeding complications. The area under the receiver operating characteristic curve (AUROC) of Model I was 0.670, whereas that of Model II increased to 0.803, demonstrating better performance with the inclusion of genetic factors. Using the significant variables in Model II, a risk scoring system was constructed. The predicted bleeding risks for scores of 0, 1-2, 3-4, 5-6, 7-8, and 9-10 points were 0%, 1.2%, 4.6%, 15.7%, 41.7%, and 73.3%, respectively. Conclusion: This study revealed an association between RYR2 and bleeding complications among patients taking DOACs and established a risk scoring system to support individualized DOAC treatment for these patients.

Machine learning-based prediction of risk factors for abnormal glycemic control in diabetic cancer patients receiving nutrition support: a case-control study.

PURPOSE: To date, risk factors affecting abnormal glycemic control have not been investigated. This study aimed to analyze risk factors for hypoglycemia or hyperglycemia in diabetic cancer patients receiving nutritional support by using machine learning methods. METHODS: This retrospective two-center study was performed using medical records. Odds ratios and adjusted odds ratios were estimated from univariate and multivariate analyses, respectively. Machine learning algorithms, including five-fold cross-validated multivariate logistic regression, elastic net, and random forest, were developed to predict risk factors for hypoglycemia and hyperglycemia. RESULTS: Data from 127 patients were analyzed. The use of sulfonylurea (SU) and blood urea nitrogen (BUN) level > 20 mg/dL increased hypoglycemia by 6.3-fold (95% CI 1.30-30.47) and 5.0-fold (95% CI 1.06-23.46), respectively. In contrast, patients who received an actual energy intake/total energy expenditure (TEE) ≥ 120% and used dipeptidyl peptidase-4 (DPP-4) inhibitors had a higher risk of hyperglycemia by 19.3- (95% CI 1.46-254.78) and 3.3-fold (95% CI 1.23-8.61), respectively. An initial blood glucose level ≥ 182.5 mg/dL also increased the risk of hyperglycemia by 15.3-fold. AUROC values for all machine learning methods indicated acceptable and excellent performance for hypoglycemia and hyperglycemia. CONCLUSION: The use of SU and BUN level > 20 mg/dL increased the risk of hypoglycemia, whereas an initial blood glucose level ≥ 182.5 mg/dL, a supplied actual energy intake/ TEE ≥ 120%, and the use of DPP-4 inhibitors increased the risk of hyperglycemia.

Association between SLCO1B1 genetic polymorphisms and bleeding risk in patients treated with edoxaban.

Since SLCO1B1 encodes the uptake transporter OATP1B1, which can influence the pharmacokinetic and pharmacodynamic profiles of edoxaban, polymorphisms in SLCO1B1 may affect the edoxaban response. This study aimed to investigate the association between SLCO1B1 gene polymorphisms and the bleeding risk in patients receiving edoxaban. We genotyped 10 single-nucleotide polymorphisms (SNPs) from the SLCO1B1 gene in patients receiving edoxaban. We also analyzed rs3842 of ABCB1 as a confounder. The odds ratio (OR) and adjusted OR (AOR) were calculated from univariate and multivariable analysis, respectively. The area under the receiver operating characteristic curve (AUROC) was constructed for the discrimination of the model. A total of 159 patients receiving edoxaban were analyzed. Overdose and rs4149056 showed significant association with bleeding complications by around 11- and 5.5-fold, respectively. Additionally, patients with the rs4149057 variant allele (C) had a 3.9-fold increased bleeding risk compared with wild-type homozygote carriers (TT), whereas rs2306283 variant homozygote (GG) carriers had a 0.27-fold reduced bleeding risk compared with wild-type allele (A) carriers. Patients with the variant-type homozygote (CC) of ABCB1 rs3842 had a higher bleeding risk than T allele carriers (AOR = 5.3 and 5.9). The final models for multivariable analyses were acceptable based on the AUROC values (> 0.70). These findings may help predict bleeding risk in patients taking edoxaban and help personalize treatment.

ABCG2 Gene Polymorphisms May Affect the Bleeding Risk in Patients on Apixaban and Rivaroxaban.

Purpose: Direct oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation. However, they have a bleeding complication. Breast cancer resistance protein, encoded by ABCG2, is known to be an efflux transporter of apixaban and rivaroxaban among DOACs. This study aimed to investigate the association between gene variants and bleeding complications during treatment with ABCG2 substrates (apixaban and rivaroxaban). Patients and Methods: Patients treated with apixaban and rivaroxaban were enrolled from June 2018 to December 2021. Five single nucleotide polymorphisms (SNPs) of ABCG2 were selected. Previously studied genes (ABCB1, CYP3A4, and CYP3A5) were further analyzed as possible confounders. Finally, a total of 16 SNPs were examined in this case-control study. The outcome was defined as major bleeding and clinically relevant non-major bleeding. Two models were constructed using the multivariable analysis. Results: Among 293 patients, 64 were cases. The mean age of the patients was 68.8 years, and males comprised 62.5% of the study population. Model I revealed that a history of bleeding, concurrent use of proton pump inhibitor (PPI), ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications; the AORs (95% CI) were 6.209 (2.210-17.442), 2.385 (1.064-5.349), 2.188 (1.156-4.142), and 3.243 (1.371-7.671), respectively. Model II showed that modified HAS-BLED score, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications. Conclusion: The modified HAS-BLED score, a history of bleeding, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with the risk of bleeding complications in patients on apixaban and rivaroxaban, after adjusting for other confounders. These findings can be used to develop individualized treatment strategies for patients taking apixaban and rivaroxaban.

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.

Comparison of pharmacogenomic information for drug approvals provided by the national regulatory agencies in Korea, Europe, Japan, and the United States.

Pharmacogenomics, which is defined as the study of changes in the properties of DNA and RNA associated with drug response, enables the prediction of the efficacy and adverse effects of drugs based on patients' specific genetic mutations. For the safe and effective use of drugs, it is important that pharmacogenomic information is easily accessible to clinical experts and patients. Therefore, we examined the pharmacogenomic information provided on drug labels in Korea, Europe, Japan, and the United States (US). The selection of drugs that include pharmacogenomic information was based on the drug list that includes genetic information from the Korea Ministry of Food and Drug Safety (MFDS) and US Food and Drug Administration (FDA) websites. Drug labels were retrieved from the sites of MFDS, FDA, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency. Drugs were classified as per the Anatomical Therapeutic Chemical code, and the biomarkers, labeling sections, and necessity of genetic tests were determined. In total, 348 drugs were selected from 380 drugs with available pharmacogenomic information in Korea and the US after applying the inclusion and exclusion criteria. Of these drugs, 137, 324, 169, and 126 were with pharmacogenomics information in Korea, the US, Europe, and Japan, respectively. The most commonly represented drug class was antineoplastic and immunomodulating agents. Regarding the classification as per the mentioned biomarkers, the cytochrome P450 enzyme was the most frequently mentioned information, and the targeted anticancer drugs most commonly required genetic biomarker testing. The reasons for differences in drug labeling information based on country include differences in mutant alleles according to ethnicity, frequencies at which drug lists are updated, and pharmacogenomics-related guidelines. Clinical experts must continuously strive to identify and report mutations that can explain drug efficacy or side effects for safe drug use.

Risk Factors for Palbociclib-Induced Early Developing Neutropenia in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.

PURPOSE: This study aimed to determine the risk factors for palbociclib-induced grade 4 or grade 3 neutropenia (NP) requiring dose reduction or delayed treatment in patients with HR+/HER2-metastatic breast cancer in the first 3 cycles (early grade 3/4 NP) and whether the early developing grade 3/4 NP affects progression-free survival. METHODS: A retrospective study using electronic medical records was conducted on patients who received palbociclib for metastatic breast cancer between January 2018 and August 2022. The early grade 3/4 NP risk factors were evaluated with univariate and multivariable logistic regression analyses. In addition, the Kaplan-Meier method was used to estimate the median progression-free survival (PFS) to analyze the effect of early grade 3/4 NP on treatment. RESULTS: Out of the 264 patients included in this study, 173 (65.6%) experienced early grade 3/4 NP. A total of four models were applied for multivariable analysis to identify early grade 3/4 NP-developing factors. Low baseline ANC, WBC, PLT, and BSA were significant risk factors for early grade 3/4 NP; baseline ANC < 3700/mm3, WBC < 6.30 × 109/mm3, PLT < 230 × 109/mm3, and BSA < 1.58 m2 increased the risk by approximately 4.0-fold, 3.7-4.0-fold, 2.1-fold, and 2.0-fold, respectively. Early grade 3/4 NP did not affect PFS (p = 0.710), although patients with early grade 3/4 NP had more frequent dose reductions or treatment delays. CONCLUSIONS: Based on the results, low baseline ANC, WBC, PLT, and BSA were associated with early grade 3/4 NP. Patients with risk factors require careful monitoring, and this study is expected to help predict NP, which may appear in early treatment.

Global Research Trends of Gender-Related Artificial Intelligence in Medicine Between 2001-2020: A Bibliometric Study.

This study aimed to assess the research on medical Artificial intelligence (AI) related to sex/gender and explore global research trends over the past 20 years. We searched the Web of Science (WoS) for gender-related medical AI publications from 2001 to 2020. We extracted the bibliometric data and calculated the annual growth of publications, Specialization Index, and Category Normalized Citation Impact. We also analyzed the publication distributions by institution, author, WoS subject category, and journal. A total of 3,110 papers were included in the bibliometric analysis. The number of publications continuously increased over time, with a steep increase between 2016 and 2020. The United States of America and Harvard University were the country and institution that had the largest number of publications. Surgery and urology nephrology were the most common subject categories of WoS. The most occurred keywords were machine learning, classification, risk, outcomes, diagnosis, and surgery. Despite increased interest, gender-related research is still low in medical AI field and further research is needed.

Effect of ITPA Polymorphism on Adverse Drug Reactions of 6-Mercaptopurine in Pediatric Patients with Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis.

6-Mercaptopurine (6-MP) is a cornerstone of the maintenance regimen for pediatric acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphatase (ITPA) is considered a candidate pharmacogenetic marker that may affect metabolism and 6-MP-induced toxicities; however, the findings are inconsistent. Therefore, we attempted to evaluate the effect of ITPA 94C>A polymorphism on 6-MP-induced hematological toxicity and hepatotoxicity through a systematic review and meta-analysis. A literature search for qualifying studies was conducted using the PubMed, Web of Science, and Embase databases until October 2021. Overall, 10 eligible studies with 1072 pediatric ALL patients were included in this meta-analysis. The results indicated that ITPA 94C>A was significantly associated with 6-MP-induced neutropenia (OR 2.38, 95% CI: 1.56−3.62; p = 0.005) and hepatotoxicity (OR 1.98, 95% CI: 1.32−2.95; p = 0.0009); however, no significant association was found between the ITPA 94C>A variant and 6-MP-induced leukopenia (OR 1.75, 95% CI: 0.74−4.12; p = 0.20). This meta-analysis demonstrated that ITPA 94C>A polymorphism could affect 6-MP-induced toxicities. Our findings suggested that ITPA genotyping might help predict 6-MP-induced myelosuppression and hepatotoxicity.

A Risk Scoring System Utilizing Machine Learning Methods for Hepatotoxicity Prediction One Year After the Initiation of Tyrosine Kinase Inhibitors.

Background: There is currently no method to predict tyrosine kinase inhibitor (TKI) -induced hepatotoxicity. The purpose of this study was to propose a risk scoring system for hepatotoxicity induced within one year of TKI administration using machine learning methods. Methods: This retrospective, multi-center study analyzed individual data of patients administered different types of TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib) selected in five previous studies. The odds ratio and adjusted odds ratio from univariate and multivariate analyses were calculated using a chi-squared test and logistic regression model. Machine learning methods, including five-fold cross-validated multivariate logistic regression, elastic net, and random forest were utilized to predict risk factors for the occurrence of hepatotoxicity. A risk scoring system was developed from the multivariate and machine learning analyses. Results: Data from 703 patients with grade II or higher hepatotoxicity within one year of TKI administration were evaluated. In a multivariable analysis, male and liver metastasis increased the risk of hepatotoxicity by 1.4-fold and 2.1-fold, respectively. The use of anticancer drugs increased the risk of hepatotoxicity by 6.0-fold. Patients administered H2 blockers or PPIs had a 1.5-fold increased risk of hepatotoxicity. The area under the receiver-operating curve (AUROC) values of machine learning methods ranged between 0.73-0.75. Based on multivariate and machine learning analyses, male (1 point), use of H2 blocker or PPI (1 point), presence of liver metastasis (2 points), and use of anticancer drugs (4 points) were integrated into the risk scoring system. From a training set, patients with 0, 1, 2-3, 4-7 point showed approximately 9.8%, 16.6%, 29.0% and 61.5% of risk of hepatotoxicity, respectively. The AUROC of the scoring system was 0.755 (95% CI, 0.706-0.804). Conclusion: Our scoring system may be helpful for patient assessment and clinical decisions when administering TKIs included in this study.

Association between SLCO1B1 polymorphism and methotrexate-induced hepatotoxicity: a systematic review and meta-analysis.

Reports on the association between the solute carrier organic anion transporter 1B1 (SLCO1B1) T521C polymorphism and methotrexate-induced hepatotoxicity in patients with malignancies are inconsistent. This meta-analysis evaluated the association between the SLCO1B1 T521C polymorphism and methotrexate-induced hepatotoxicity. We performed a systematic review of previous reports from the PubMed, Web of Science, and EMBASE databases, and a meta-analysis was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated to evaluate the effect of the SLCO1B1 T521C polymorphism on the occurrence of methotrexate-induced hepatotoxicity. In total, data from five studies including 465 patients were analyzed. Patients had received a high-dose methotrexate regimen (1-5 g/m2). The SLCO1B1 variant allele (C allele) carriers had a 1.9-fold higher risk of hepatotoxicity than wild-type homozygote carriers (TT; OR, 1.94; 95% CI, 1.14-3.31). This meta-analysis demonstrated that C allele carriers of the SLCO1B1 polymorphism had a higher risk of hepatotoxicity than patients with the TT genotype. The SLCO1B1 T521C polymorphism may be a useful predictor for methotrexate-induced hepatotoxicity in patients with malignancies.

Machine Learning Approaches to Predict Hepatotoxicity Risk in Patients Receiving Nilotinib.

Background: Although nilotinib hepatotoxicity can cause severe clinical conditions and may alter treatment plans, risk factors affecting nilotinib-induced hepatotoxicity have not been investigated. This study aimed to elucidate the factors affecting nilotinib-induced hepatotoxicity. Methods: This retrospective cohort study was performed on patients using nilotinib from July of 2015 to June of 2020. We estimated the odds ratio and adjusted odds ratio from univariate and multivariate analyses, respectively. Several machine learning models were developed to predict risk factors of hepatotoxicity occurrence. The area under the curve (AUC) was analyzed to assess clinical performance. Results: Among 353 patients, the rate of patients with grade I or higher hepatotoxicity after nilotinib administration was 40.8%. Male patients and patients who received nilotinib at a dose of ≥300 mg had a 2.3-fold and a 3.5-fold increased risk for hepatotoxicity compared to female patients and compared with those who received <300 mg, respectively. H2 blocker use decreased hepatotoxicity by 11.6-fold. The area under the curve (AUC) values of machine learning methods ranged between 0.61-0.65 in this study. Conclusion: This study suggests that the use of H2 blockers was a reduced risk of nilotinib-induced hepatotoxicity, whereas male gender and a high dose were associated with increased hepatotoxicity.

Analysis of Risk Factors for Hepatotoxicity Induced by Immune Checkpoint Inhibitors.

Although hepatotoxicity induced by immune checkpoint inhibitors (ICPIs) can cause severe clinical complications, the risk factors associated with hepatotoxicity have rarely been investigated. The purpose of this study was to determine the potential risk factors for the incidence of hepatotoxicity and for time to ICPI-induced hepatotoxicity. Patients who received ICPIs (atezolizumab, nivolumab, pembrolizumab, and ipilimumab) were included in this retrospective 2-center study. Collected data included sex, age, body weight, body surface area, Eastern Cooperative Oncology Group performance status, underlying disease, liver metastasis, programmed cell death ligand-1 expression, interval from previous chemotherapy, and concomitant drug use. Among the 194 patients, patients who experienced hepatotoxicity after ICPI administration was 64.4% (n=125) in all grade and 10.8% (n=21) in grade III or higher. Multivariate analysis showed that patients aged 30-50 and 50-70 years had increased risks of hepatotoxicity by 4.9-fold (95% confidence interval, 1.3-18.0) and 2.7-fold (95% confidence interval, 1.3-5.5), respectively, compared with those older than 70 years. The use of acetaminophen increased the occurrence of hepatotoxicity by 2.1 times; the attributable risk was 53.2%. Male patients and patients younger than 65 years had around 1.5-fold increased hazard of time to reach hepatotoxicity. Patients treated with 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors had a 4.7-fold higher risk of grade III-IV hepatotoxicity compared with those without HMG-CoA reductase inhibitors; the attributable risk was 78.8%. In conclusion, close monitoring of liver function is recommended, especially in male patients, patients younger than 65 years old, and when there is concomitant use of hepatotoxic drugs including acetaminophen and HMG-CoA reductase inhibitors.

Factors affecting high-grade hepatotoxicity of tyrosine kinase inhibitors in cancer patients: a multi-center observational study.

PURPOSE: Although several studies have examined tyrosine kinase inhibitor (TKI)-induced hepatotoxicity, the majority of patients in those studies displayed low-grade (grade I-II) hepatotoxicity. The purpose of this study was to investigate factors affecting high-grade (grade III-IV) hepatotoxicity of TKIs. METHODS: This multi-center, retrospective study used individual patient data from five studies that examined factors affecting hepatotoxicity by TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib). Odds ratio (OR) and adjusted OR (AOR) were estimated from univariate and multivariate analyses, respectively. RESULTS: Data from 1279 patients treated with TKIs were analyzed. The rate of patients who experienced high-grade hepatotoxicity after TKI administration was 5.5%. In multivariable analysis, H2 blockers and CYP3A4 inducers increased high-grade hepatotoxicity 2.2- (95% CI 1.255-3.944) and 3.3-fold (95% CI 1.260-8.698), respectively. Patients with liver metastasis revealed a 3.4-fold (95% CI 1.561-7.466) higher risk of high-grade hepatotoxicity. Among underlying malignancies, pancreatic cancer and other cancers including acute lymphoblastic leukemia increased the risk of high-grade hepatotoxicity by 2.6- and 24.3-fold, respectively, whereas breast cancer decreased the risk (AOR 0.3, 95% CI 0.106-0.852), compared to non-small cell lung cancer. In patients who administrated TKIs which form reactive metabolites, use of CYP3A4 inducers and liver metastasis increased incidence of high-grade hepatotoxicity by 3.0- and 2.3-fold, respectively. In patients with EGFR mutation, exon 19 deletion and use of proton pump inhibitors were risk factors for high-grade hepatotoxicity in addition to liver metastasis and use of H2 blockers. CONCLUSION: The use of H2 blockers, presence of liver metastasis, and CYP3A4 inducers were associated with high-grade hepatotoxicity of TKIs. In subgroup analyses, presence of exon 19 deletion, and/or proton pump inhibitors, was additional risk factors for high-grade hepatotoxicity in special patients and use of specific TKIs. Close liver function monitoring is recommended, especially in patients with liver metastasis or using H2 blockers or CYP3A4 inducers.

Low cyclosporine concentrations in children and time to acute graft versus host disease.

BACKGROUND: Achievement of target blood concentrations of cyclosporine (CsA) early after transplantation is known to be highly effective for reducing the incidence of acute graft versus host disease (aGVHD). However, no research has been conducted for predicting aGVHD occurrence with low CsA concentrations at different time periods. The objective of this study was to investigate the risk of aGVHD according to low CsA concentrations at lag days in children with allogenic hematopoietic stem cell transplantation (HSCT). METHODS: The records of 61 consecutive children who underwent allogeneic HSCT and received CsA as prophylaxis against aGVHD between May 2012 and March 2015 were retrospectively evaluated. The main outcome was any association between low CsA concentrations at lag days and aGVHD occurrence, which was examined for the first month after transplantation. Mean CsA concentrations at three lag periods were calculated: lag days 0-6, 7-13, and 14-20 before aGVHD occurrence. RESULTS: Patients whose mean CsA concentrations at lag days 0-6 did not reach the initial target concentration had 11.0-fold (95% confidence interval [CI]: 2.3-51.9) greater incidence of aGVHD. In addition, the AORs of low CsA concentrations at lag days 7-13 and 14-20 for developing aGVHD were 108.2 (95% CI: 7.7-1515.5) and 12.1 (95% CI: 1.1-138.1), respectively. CONCLUSIONS: After low CsA concentrations are detected, careful attention needs to be paid to prevent aGVHD.

Influence of CYP2C9 and CYP2A6 on plasma concentrations of valproic acid: a meta-analysis.

PURPOSE: Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However, the correlation between plasma VPA concentrations and CYP2C9 and CYP2A6 gene variations is uncertain. This meta-analysis aimed to investigate the relationship between CYP2C9 and CYP2A6 variants and plasma concentrations of VPA. METHODS: The PubMed, Web of Science, and EMBASE databases were searched for qualifying studies published until July 2019. Cohort studies that included standardized plasma VPA concentrations and CYP2C9 and CYP2A6 genotypes were reviewed. The mean difference and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. Data analysis was performed using Review Manager (version 5.3) and RStudio (version 3.6). RESULTS: In total, we analyzed data from six studies involving 807 patients. We found that CYP2C9*3 was associated with standardized plasma VPA concentration; *3 allele carriers had a 0.70-µg/mL higher concentration per mg/kg than non-carriers (95% CI 0.25, 1.15; P = 0.002). We also found a significant association between the CYP2A6*4 and standardized trough VPA concentration; patients with the *4 allele had a 0.48-µg/mL higher concentration per mg/kg than patients without the *4 allele (95% CI 0.10, 0.86; P = 0.01). CONCLUSION: This meta-analysis demonstrated that CYP2C9*3 and CYP2A6*4 genetic variants affect plasma VPA concentrations. For epilepsy patients with these genotypes, dose adjustment may be necessary to ensure VPA's therapeutic effect.

Efficacy and safety of clopidogrel versus prasugrel and ticagrelor for coronary artery disease treatment in patients with CYP2C19 LoF alleles: a systemic review and meta-analysis.

AIM: We performed a systematic review and meta-analysis to compare the efficacy and safety of ticagrelor and prasugrel with those of clopidogrel in CYP2C19 reduced-metabolizers. METHODS: PubMed, Cochrane and Web of Science were systematically searched for randomized controlled trials or cohort studies up to January 2020. The primary endpoint was major adverse cardiovascular events (MACE), including cardiovascular (CV) death, all-cause death, myocardial infarction (MI), stent thrombosis and stroke. The secondary endpoint was bleeding. Pooled effects were measured by relative risk (RR) with 95% confidence intervals (CIs). Publication bias was evaluated with Egger's regression test and adjusted by trim and fill method. RESULTS: Twelve studies comprising 5829 CV patients with CYP2C19 loss-of-function alleles were included. Patients who received ticagrelor or prasugrel showed a lower risk of MACE than those who received clopidogrel (RR 0.524; 95% CI: 0.375, 0.731). The former also had lower risks of CV death (RR 0.409; 95% CI: 0.177, 0.946), all-cause death (RR 0.441; 95% CI: 0.263, 0.739), MI (RR 0.554; 95% CI: 0.414, 0.741) and stent thrombosis (RR 0.587; 95% CI: 0.348, 0.988) than the latter patient group. The risk of stroke was not significantly different between patients receiving the alternatives and those receiving clopidogrel (RR 0.605; 95% CI: 0.257, 1.425). Major and minor bleeding risk was not significantly different between patients treated with alternatives and clopidogrel (RR 1.019; 95% CI: 0.827, 1.260 and RR 1.235; 95% CI: 0.581, 2.628, respectively). CONCLUSION: CYP2C19 reduced-metabolizers can expect better clinical outcome on using prasugrel or ticagrelor rather than clopidogrel.

Risk factors for sodium overcorrection in non-hypovolemic hyponatremia patients treated with tolvaptan.

PURPOSE: In this study, the risk factors associated with sodium overcorrection were investigated with an optimal cutoff for baseline serum sodium for use in daily clinical practice. METHODS: Electronic medical records of patients who received tolvaptan for non-hypovolemic hyponatremia were reviewed. Demographic and clinical data including age, sex, weight, height, comorbidity, cause of hyponatremia, hypertonic saline use, and comedication were collected. Baseline laboratory parameters measured included serum sodium, serum potassium, serum creatinine, blood urea nitrogen, serum tonicity, ALT, AST, and urine osmolality. The primary outcome was the overcorrection of serum sodium, which was defined as an increase in serum sodium by more than 10 mmol/L in 24 h. RESULTS: From a total of 77 patients included in the analysis, 24 (31.2%) showed sodium overcorrection (> 10 mmol/L/24 h); 2 (2.6%) in heart failure cohort, 17 (22.1%) in SIADH cohort, and 5 (6.5%) in unknown cause cohort. More than half of patients (51.9%) were administered hypertonic saline prior to tolvaptan. Hypertension, cancer, diuretics, baseline serum sodium, and SIADH were associated with the risk of overcorrection in the univariable analysis. Significant factors for the overcorrection from multivariable analysis were lower body mass index, presence of cancer (adjusted odds ratio, 10.87; 95% CI, 1.23-96.44), and lower serum sodium at baseline (adjusted odds ratio, 0.76 for every 1 mEq/L increase; 95% CI, 0.61-0.94). CONCLUSION: The overcorrection of hyponatremia in non-hypovolemic patients treated with tolvaptan was significantly associated with lower body mass index, presence of cancer, and lower serum sodium at baseline. In subgroup analysis using SIADH patients, baseline sodium and cancer were found to be significant factors of overcorrection.

Health Behaviors Associated with Aggression in Korean Adolescents: Data from 2 Cross-sectional Studies.

Objectives: In this study, we identified the health-related behaviors associated with aggression and examined the trends in both aggression and health-related behaviors among adolescents in the Republic of Korea. Methods: We used 2 cross-sectional samples of adolescents collected from the same geographic region 10 years apart. We measured aggression using the Aggression Questionnaire. Subject characteristics of the questionnaire included age, sex, caffeine intake, alcohol consumption, smoking, regular exercise, use of medications, and unstable mood. Results: Data pertaining to 1316 and 894 students were extracted from 2006 and 2016 surveys, respectively. Based on the multivariate results, sex and smoking were associated with physical aggression in both surveys, whereas sex and unstable mood were linked to verbal aggression. Alcohol consumption, unstable mood, and use of pain medications were related to anger; indigestion and unstable mood were associated with hostility in both years. The total aggression score was significantly related to alcohol consumption and unstable mood in both years after adjusting for other confounders. Conclusions: Health-related behaviors such as alcohol consumption and unstable mood showed meaningful relations with aggression. Accordingly, we should increase public awareness of factors associated with aggression, and government agencies and schools should implement comprehensive prevention efforts.