Background: Patients with multivessel coronary spasm showed relatively poor outcomes in vasospastic angina. Recent report also revealed that Ergovonine response definite group showed poor clinical outcomes compared to the Ergovonine response intermediate group. The purpose of this study is to evaluate the clinical impact of Ergovonine provocation definite or intermediate response in multivessel vasospastic angina patients. Methods: A total of 428 patients between May 2010 to November 2013, diagnosed as multivessel vasospastic angina who were registered in the Vasospastic Angina Korea (VA-KOREA) were enrolled. Patients were divided into Ergovonine provocation response definite group (n=111) and intermediate group (n=317). The primary endpoint was cumulative incidece of cardiac death, new onset arrhythmia, acute coronary syndrome, re-admission due to chest pain during 3 years follow-up. Results: In the baseline clinical chracteristics, Ergovonine response definite group had less proportion of male patients (32.4% vs. 49.8%, p=0.002). Other conventional cardiovascular risk factors were similar between two groups. In the angiographic characteristics, electrocardiogram changes during Ergovonine provocation was higher in the deinite group including ST change (18% vs 10.7%; p=0.046), ST elevation (16.2% vs 2.8%; p<0.001), ST depression (7.2% vs 2.5%; p=0.009), induced arrhythmia (27.9% vs 15.5%; p=0.004). Combined atherosclerotic lesion was also higher in the definite group (29.7% vs 15.5%; p=0.001). Prescrpition rate of Calcium channel blocker was lower in the intermediate group compared to the definite group (93.7% vs. 83.6%; p=0.008). The incidence of primary end point was not statistically signficant in both groups (10.8% vs. 14.5%; p=0.327). Multivariative cox regression analysis revealed that Ergovonine provocation response had no significant clinical impact in multivessel vasospastic angina patients (adjusted harzard ratio [HR] 0.64; 95% confidence interval [CI] 0.32 – 1.28; p=0.207). Conclusion: The present study indicates that Ergovonine provocation response is not an independent prognostic factor in multivessel vasospastic angina patients. Thus, intensive medical treatment and risk control should be carried out in both patient groups.

Introduction Variations in the NUDT15 and TPMT genes, which serve as pharmacogenomic markers for 6-mercaptopurine (6MP), contribute to individual differences in the optimal dosage of this medication. Nevertheless, given the observed difference in the tolerated dose of 6MP between East Asian and Western patients, it is essential to conduct a study to determine whether the same dosage guidelines are applicable to both populations. This study aimed to reduce treatment discontinuation and neutropenia during maintenance by adjusting the initial dose of 6MP based on the results of the NUDT15 or TPMT variants. M ethods This is a prospective phase II trial being conducted at three institutions in Korea. Patients who initiated 6MP-based maintenance treatment for acute lymphoblastic leukemia (ALL) were included in the study. During the maintenance phase, 6MP was administered at an individualized starting dose based on the NUDT15 and TPMT variants of each participant. Original dose (50 mg/m 2/day) of 6MP was administered to patients with both NUDT15 and TPMT wild-type, 30 mg/m 2/day for NUDT15 intermediate activity ( NUDT15 variant allele heterozygous) or TPMT heterozygosity, 10 mg/m 2/day for NUDT15 low activity ( NUDT15 variant allele homozygous), and 10 mg/m 2/day three times per week for homozygous TPMT variants. The maintenance cycle consists of 12 weeks of daily 6MP at an individualized dosage, weekly methotrexate (MTX) at a dosage of 20 mg/m 2, and monthly vincristine and steroid pulses. Lastly, intrathecally administered MTX is administered every three months. During treatment, the total white blood cell count was targeted to be between 2000/uL and 3000/uL, with an absolute neutrophil count greater than 500/uL and a platelet count greater than 50,000/uL. The whole exome was sequenced using genomic DNA extracted from peripheral blood at complete remission or hair follicles. As the primary and secondary endpoints, the duration of treatment discontinuation, the frequency of neutropenia, the presence of neutropenic fever during maintenance therapy, and the recurrence rate were compared to historical controls. A cohort of 254 patients who underwent maintenance therapy between the years 2001 and 2018 was chosen as the historical control group. Results Total 72 patients were enrolled from July 2019 until Aril 2022. This analysis was conducted on 52 patients who finished maintenance therapy. There were 32 males, and 20 females. The median age of the patients was 5.6 years (range, 2.2~15.9 years). The immunophenotypes of ALL was B-ALL in 40 patients, T-ALL in 10, Mixed phenotype in 1, and unspecified ALL in 1 patient. No patient had known pharmacogenetic variants in TPMT. The NUDT15phenotypes based on diplotypes included normal activity (n=41), intermediate activity (n=9), and low activity (n=2), occurring in 78.8%, 17.3%, and 3.8% respectively (Table 1). The number of days discontinued due to any toxicity during the 1 st cycle of maintenance therapy was average 7 days (max 59 days) in all patients, and that of the study group with intermediate enzyme activity phentypes was significantly shorter than in historical controls, with an average 6 days vs. 12 days ( P=0.03, Figure 1). The incidence of neutropenia during the 1 st cycle between two groups was not statistically different, however, among patients with NUDT15 or TPMT intermediate activity, the frequency of neutropenia was significantly lower in the study group ( P=0.03, Figure 2). The frequency of neutropenic fever (NF) and fever without neutropenia during the 1st cycle did not differ between the two groups. However, when patients with NUDT15 or TPMT intermediate activity were analyzed, no fever occurred in the study group of 9 patients, while NF and fever occurred in 11 and 8 patients in the control group (Figure 3). Conclusions Individualized administration of 6MP based on NUDT15 and TPMT genotypes during maintenance therapy in Korean pediatric ALL patients significantly reduced treatment discontinuation and febrile toxicity. A decrease in the initial dosage from 50 mg/m 2/day to 30 mg/m 2/day has the potential to reduce febrile toxicity in the patient group exhibiting intermediate activity of the NUDT15 enzyme, which is observed in approximately 20% of individuals in East Asia. Through this research, we expect to provide the dosing guidelines for 6MP in patients with ALL in East Asia.

Background: Patients with multivessel coronary spasm showed relatively poor outcomes in vasospastic angina. Recent report also revealed that Ergovonine response definite group showed poor clinical outcomes compared to the Ergovonine response intermediate group. The purpose of this study is to evaluate the clinical impact of Ergovonine provocation definite or intermediate response in multivessel vasospastic angina patients. Methods: A total of 428 patients between May 2010 to November 2013, diagnosed as multivessel vasospastic angina who were registered in the Vasospastic Angina Korea (VA-KOREA) were enrolled. Patients were divided into Ergovonine provocation response definite group (n=111) and intermediate group (n=317). The primary endpoint was cumulative incidece of cardiac death, new onset arrhythmia, acute coronary syndrome, re-admission due to chest pain during 3 years follow-up. Results: In the baseline clinical chracteristics, Ergovonine response definite group had less proportion of male patients (32.4% vs. 49.8%, p=0.002). Other conventional cardiovascular risk factors were similar between two groups. In the angiographic characteristics, electrocardiogram changes during Ergovonine provocation was higher in the deinite group including ST change (18% vs 10.7%; p=0.046), ST elevation (16.2% vs 2.8%; p<0.001), ST depression (7.2% vs 2.5%; p=0.009), induced arrhythmia (27.9% vs 15.5%; p=0.004). Combined atherosclerotic lesion was also higher in the definite group (29.7% vs 15.5%; p=0.001). Prescrpition rate of Calcium channel blocker was lower in the intermediate group compared to the definite group (93.7% vs. 83.6%; p=0.008). The incidence of primary end point was not statistically signficant in both groups (10.8% vs. 14.5%; p=0.327). Multivariative cox regression analysis revealed that Ergovonine provocation response had no significant clinical impact in multivessel vasospastic angina patients (adjusted harzard ratio [HR] 0.64; 95% confidence interval [CI] 0.32 – 1.28; p=0.207). Conclusion: The present study indicates that Ergovonine provocation response is not an independent prognostic factor in multivessel vasospastic angina patients. Thus, intensive medical treatment and risk control should be carried out in both patient groups.

Introduction Variations in the NUDT15 and TPMT genes, which serve as pharmacogenomic markers for 6-mercaptopurine (6MP), contribute to individual differences in the optimal dosage of this medication. Nevertheless, given the observed difference in the tolerated dose of 6MP between East Asian and Western patients, it is essential to conduct a study to determine whether the same dosage guidelines are applicable to both populations. This study aimed to reduce treatment discontinuation and neutropenia during maintenance by adjusting the initial dose of 6MP based on the results of the NUDT15 or TPMT variants. M ethods This is a prospective phase II trial being conducted at three institutions in Korea. Patients who initiated 6MP-based maintenance treatment for acute lymphoblastic leukemia (ALL) were included in the study. During the maintenance phase, 6MP was administered at an individualized starting dose based on the NUDT15 and TPMT variants of each participant. Original dose (50 mg/m 2/day) of 6MP was administered to patients with both NUDT15 and TPMT wild-type, 30 mg/m 2/day for NUDT15 intermediate activity ( NUDT15 variant allele heterozygous) or TPMT heterozygosity, 10 mg/m 2/day for NUDT15 low activity ( NUDT15 variant allele homozygous), and 10 mg/m 2/day three times per week for homozygous TPMT variants. The maintenance cycle consists of 12 weeks of daily 6MP at an individualized dosage, weekly methotrexate (MTX) at a dosage of 20 mg/m 2, and monthly vincristine and steroid pulses. Lastly, intrathecally administered MTX is administered every three months. During treatment, the total white blood cell count was targeted to be between 2000/uL and 3000/uL, with an absolute neutrophil count greater than 500/uL and a platelet count greater than 50,000/uL. The whole exome was sequenced using genomic DNA extracted from peripheral blood at complete remission or hair follicles. As the primary and secondary endpoints, the duration of treatment discontinuation, the frequency of neutropenia, the presence of neutropenic fever during maintenance therapy, and the recurrence rate were compared to historical controls. A cohort of 254 patients who underwent maintenance therapy between the years 2001 and 2018 was chosen as the historical control group. Results Total 72 patients were enrolled from July 2019 until Aril 2022. This analysis was conducted on 52 patients who finished maintenance therapy. There were 32 males, and 20 females. The median age of the patients was 5.6 years (range, 2.2~15.9 years). The immunophenotypes of ALL was B-ALL in 40 patients, T-ALL in 10, Mixed phenotype in 1, and unspecified ALL in 1 patient. No patient had known pharmacogenetic variants in TPMT. The NUDT15phenotypes based on diplotypes included normal activity (n=41), intermediate activity (n=9), and low activity (n=2), occurring in 78.8%, 17.3%, and 3.8% respectively (Table 1). The number of days discontinued due to any toxicity during the 1 st cycle of maintenance therapy was average 7 days (max 59 days) in all patients, and that of the study group with intermediate enzyme activity phentypes was significantly shorter than in historical controls, with an average 6 days vs. 12 days ( P=0.03, Figure 1). The incidence of neutropenia during the 1 st cycle between two groups was not statistically different, however, among patients with NUDT15 or TPMT intermediate activity, the frequency of neutropenia was significantly lower in the study group ( P=0.03, Figure 2). The frequency of neutropenic fever (NF) and fever without neutropenia during the 1st cycle did not differ between the two groups. However, when patients with NUDT15 or TPMT intermediate activity were analyzed, no fever occurred in the study group of 9 patients, while NF and fever occurred in 11 and 8 patients in the control group (Figure 3). Conclusions Individualized administration of 6MP based on NUDT15 and TPMT genotypes during maintenance therapy in Korean pediatric ALL patients significantly reduced treatment discontinuation and febrile toxicity. A decrease in the initial dosage from 50 mg/m 2/day to 30 mg/m 2/day has the potential to reduce febrile toxicity in the patient group exhibiting intermediate activity of the NUDT15 enzyme, which is observed in approximately 20% of individuals in East Asia. Through this research, we expect to provide the dosing guidelines for 6MP in patients with ALL in East Asia.

These findings suggest that the HRAG framework could contribute to the development of a PGx AI assistant. It may help narrow the knowledge gap and facilitate the broader adoption of PGx.

Accurate pathogenicity prediction of rare variants in coding regions is crucial for prioritizing candidate variants in human diseases and advancing personalized precision medicine. Although many prediction methods have been developed, it remains unclear how they perform specifically on rare variants. In this study, the performance of 28 pathogenicity prediction methods was assessed using the latest ClinVar dataset, with a focus on rare variants and various allele frequency (AF) ranges. Ten evaluation metrics were employed to comprehensively assess the predictive performance of each method. The methods were selected based on their training approaches, including whether the training dataset was filtered by AF and whether AF was incorporated as a feature. Most methods focused on missense and start-lost variants, covering only a subset of nonsynonymous SNVs. The average missing rate of approximately 10% was observed in these variants, indicating that prediction scores were unavailable for them. MetaRNN and ClinPred, which incorporated conservation, other prediction scores, and AFs as features, demonstrated the highest predictive power on rare variants. For most methods, specificity was lower than sensitivity. Across various AF ranges, most performance metrics tended to decline as AF decreased, with specificity showing a particularly large decline. These results provide insights into the strengths and limitations of each method in predicting the pathogenicity of rare variants, which may guide future improvements in predictive models. Furthermore, while AF and existing prediction scores offer valuable information for prediction methods, the identification of novel biological features is essential to overcome current limitations and further improve predictive performance.

<sec> <title>BACKGROUND</title> A rapidly aging population led to an increase in the number of patients with chronic diseases and polypharmacy. Although investigations on the appropriate number of drugs for older patients have been conducted, there is a shortage of studies on polypharmacy criteria in older inpatients from multiple institutions. </sec> <sec> <title>OBJECTIVE</title> The aim of this study was to examine the patterns of polypharmacy and determine the criteria for the number of drugs defining polypharmacy in the geriatric inpatient population. </sec> <sec> <title>METHODS</title> Electronic health records of 4 medical institutions for patients aged 65 years and older hospitalized between January 1, 2012, and December 31, 2020, were analyzed for the study. The maximum number of drugs prescribed was obtained for each patient and, along with a literature review, was used to determine the appropriate polypharmacy level for our population. </sec> <sec> <title>RESULTS</title> We suggest a 4-level polypharmacy category system consisting of nonpolypharmacy, polypharmacy, major polypharmacy, and excessive polypharmacy based on a review of international guidelines and polypharmacy literature. Application of this system to our study population showed that the major polypharmacy category (use of 10-19 concurrent drugs) was an appropriate threshold for polypharmacy in hospitalized patients versus the traditional threshold of 5 or more concurrent drugs. The tendency of our study population to have a higher disease and drug count supports this threshold. Frequently prescribed therapeutic subgroups in this category were antibacterials for systemic use, anesthetics, and cardiac therapy. </sec> <sec> <title>CONCLUSIONS</title> This study proposes a polypharmacy categorization system for older inpatients, which differs from the common definition of the concomitant prescription of 5 or more drugs. The older population tends to have severe conditions including those requiring major surgeries; therefore, a drug count corresponding to the definition of major polypharmacy is appropriate. </sec>

This study involving 6,248 AMI patients demonstrated that the greater the LDL-C reduction from baseline, the lower the risk of MACE. However, there was no clear decreasing trend in the risk of MACE when absolute follow-up LDL-C levels were lowered from around 70 mg/dL.

Triple‑negative breast cancer (TNBC) is a lethal subtype of breast cancer with a poor prognosis and limited existing treatment options. The immune checkpoint inhibitor, anti‑programmed death ligand 1 (PD‑L1), has recently emerged as a promising alternative in treating TNBC. PD‑L1 is critical in tumor immune evasion and is therefore a key target for cancer immunotherapy. Although anti‑PD‑L1 therapy is effective in breast cancer based on clinical trials, the relationship between PD‑L1 expression levels and treatment response remains unclear. To investigate this, a 4T1 breast cancer cell line that stably overexpressed PD‑L1 was established and was used to create a tumor model in mice. Mice were treated with anti‑PD‑L1 antibodies, and tumor growth was compared between the control and treated groups. PD‑L1 overexpressing tumors did not exhibit an antitumor response to anti‑PD‑L1 therapy compared with the control tumors. Additionally, immune cell infiltration and activation were significantly altered, as shown by immunohistochemical staining and bulk RNA sequencing. In PD‑L1‑overexpressing tumors that did not respond to treatment, immune cell markers and antitumor immune pathways were downregulated. These results demonstrated that excessive PD‑L1 expression creates an immunosuppressive tumor microenvironment, which impairs the efficacy of anti‑PD‑L1 therapy. The present study suggests that excessive PD‑L1 expression reduces the effectiveness of antitumor immunotherapy, and that PD‑L 1 expression levels are essential in predicting the response to antitumor immunotherapy.

This study proposes an initial framework for a mobile system that enhances access to welfare information for people with disabilities by addressing their needs. This approach would support people with disabilities in exercising their rights and improving their quality of life.