Comparison of cutaneous adverse events between second-generation tyrosine kinase inhibitors and imatinib for chronic myeloid leukemia: a systematic review and meta-analysis.

BACKGROUND: Patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) often experience cutaneous adverse events, such as rashes and pruritus. In this study, we aimed to compare the risks of cutaneous adverse events between imatinib- and second-generation TKI-treated patients with CML. MATERIAL AND METHODS: Paired reviewers independently obtained studies from PubMed, Embase, and Cochrane Library published until 15 March 2022. The following terms were searched: (Leukemia, Myelogenous, Chronic and BCR-ABL Positive), chronic myeloid leukemia, tyrosine kinase inhibitor, TKI, imatinib, dasatinib, nilotinib, bosutinib, and radotinib. Two independent reviewers screened the results and selected articles on cutaneous adverse events. RevMan 5.4 and the Cochrane Collaboration tool were used to perform the meta-analysis and risk of bias assessment. RESULTS AND CONCLUSION: Eleven trials involving 4502 patients were analyzed in this study. Patients treated with second-generation TKIs were significantly more likely to experience cutaneous adverse events than those treated with imatinib with a relative risk (RR) of 1.62 (95% confidence interval [CI], [1.25-2.09]). Except dasatinib (RR [95% CI], 1.39 [0.75-2.56]), the risk of adverse events was more with second-generation TKIs than with imatinib as follows: nilotinib (2.11 [1.53-2.90]), bosutinib (1.41 [1.07-1.86]), and radotinib (1.87 [1.33-2.63]). Rash was the most common cutaneous adverse event that was observed in 21.6% of cases across all grades, followed by pruritus (5.7%) and alopecia (4.3%). In conclusion, our findings suggest that cutaneous adverse events occur more frequently with second-generation TKIs than with imatinib. Therefore, effective management of the cutaneous outcome is necessary to achieve high patient adherence to medication and successful treatment with TKIs.

Objective structured clinical examination as a competency assessment tool of students' readiness for advanced pharmacy practice experiences in South Korea: a pilot study.

BACKGROUND: The assessment of pharmacy students' readiness to begin the education of an advanced pharmacy practice experience (APPE) in clinical pharmacy settings continues to gain increasing attention. This study aimed to develop an objective structured clinical examination (OSCE) in the core domains acquired through an introductory pharmacy practice experience (IPPE), for evaluating its appropriateness as a tool of assessing clinical pharmacist competency for APPEs in Korean pharmacy students throughout a pilot study. METHODS: OSCE's core competency domains and case scenarios were developed through a literature review, ideation by researchers, and external experts' consensus by a Delphi method. A prospective single-arm pilot test was conducted to implement the OSCE for Korean pharmacy students who completed a 60-h course of in-class simulation IPPE. Their competencies were assessed by four assessors in each OSCE station with a pass-fail grading system accompanied by a scoring rubric. RESULTS: OSCE competency areas including patient counseling, provision of drug information, over-the-counter (OTC) counseling, and pharmaceutical care services were developed with four interactive and one non-interactive cases. Twenty pharmacy students participated in the OSCE pilot test, and their competencies were evaluated by 20 assessors. The performance rate was the lowest in the area of patient counseling for a respiratory inhaler (32.1%) and the highest (79.7%) in OTC counseling for constipation. The students had an average performance rate of 60.4% in their communication skills. Most participants agreed on the appropriateness, necessity, and effectiveness of the OSCE in evaluating pharmacy students' clinical performance and communication skills. CONCLUSIONS: The OSCE model can be used to assess pharmacy students' readiness for off-campus clinical pharmacy practice experience. Our pilot study suggests the necessity of conducting an OSCE domain-based adjustment of difficulty levels, and strengthening simulation-based IPPE education.

Women's attitudes toward certification logos, labels, and advertisements for organic disposable sanitary pads: results from a multi-city cross-sectional survey.

BACKGROUND: This cross-sectional study evaluated women's attitudes toward the certification logos, labels, and advertisements for organic disposable sanitary pads (OSPs) and investigated what could be the main reason for them. Additionally, the present study examined whether a relationship could be found between these attitudes and OSPs purchasing behavior. METHODS: This study was conducted using a self-reported online survey of Korean adult women who have purchased OSPs. The study questionnaire had four sections, covering (1) characteristics of OSP purchasing behavior, (2) attitudes toward OSP certification logos, labels, and advertisements, (3) demand on government and companies for proper management, and (4) respondent's sociodemographic information. The Cronbach's alpha value of the questionnaire was 0.857. RESULTS: A total of 500 respondents completed the questionnaire. Overall, high reliability was found for the certification logos (3.73 ± 0.61), labels on the product packaging (3.71 ± 0.63), and advertisements of OSPs (3.41 ± 0.62). Respondents indicated that these had fairly positive effects on their decision-making regarding product reliability, product image, and their own purchasing behavior. The aspects most frequently affected from the informants were safety to human health. All attitudes toward OSP certification logos, labels, and advertisements that were evaluated in this study became more positive in the direction from non-buyers to occasional buyers and to habitual buyers (all P < 0.05). The most significant demand from the respondents for OSP companies and the government was to clearly indicate hazardous ingredients on the OSP packaging (42.0%) and to strengthen the sanctions for false advertising (37.8%), respectively. CONCLUSIONS: The results of this study clearly indicate the importance of using certification logos, labels, and advertisements in the OSP market. These results can be utilized by OSP companies to improve the effectiveness of their marketing strategies or by policy makers and certifying bodies to manage the informants properly in the OSP market.

Major Adverse Cardiovascular Events in Antidepressant Users Within Patients With Ischemic Heart Diseases: A Nationwide Cohort Study.

BACKGROUND: To evaluate the effect of antidepressants on the development of major adverse cardiovascular events (MACEs) in patients with ischemic heart disease (IHD), we analyzed the association between antidepressant use and the risk of MACE development. METHODS: Patients with depression and a history of IHD between 2008 and 2012 were identified by using the National Health Insurance Service database. A cohort was followed up for the development of MACE until the end of 2015. Hazard ratios (HRs) for myocardial infarction, stroke, and cardiovascular death were estimated by Cox proportional hazard regression in a propensity score-matched cohort. RESULTS: Over a median 4.2 years of follow-up, 2943 MACE occurred in 18,981 antidepressant users. Use of antidepressants was not associated with the incidence of MACE when compared with antidepressant nonusers (adjusted HR, 1.00; 95% confidence interval, 0.95-1.05). Among the analyses according to different classes of antidepressants, the increased risk of stroke was only observed in the subgroup of selective serotonin reuptake inhibitor (SSRI) users. Dose-response findings reported greater risk in those with higher doses of use (SSRIs with ≥1.0 defined daily dose; adjusted HR, 1.14; 95% confidence interval, 1.06-1.23), whereas duration response does not support association. CONCLUSIONS: Compared with antidepressant nonusers, use of antidepressants was not associated with occurrence of MACEs in patients with depression and IHD. Although the overall effect of antidepressants on the risk of MACE was neutral, careful monitoring of MACE development is recommended in high-dose SSRI users.

Nationwide prevalence of potential drug-drug interactions associated with non-anticancer agents in patients on oral anticancer agents in South Korea.

PURPOSE: We analyzed the prevalence and severity of potential drug-drug interactions (PDDIs) in Korean patients receiving oral anticancer agents (OAAs) during two different periods. METHODS: A cross-sectional study was conducted using the national insurance reimbursement database. The subjects were adult outpatients diagnosed with cancer and prescribed OAAs at least once in 2010 or 2014. PDDIs were identified using a database and the PDDI severity was categorized as category X (contraindications) or D (consideration of therapy modification). The associated factors for the occurrence of PDDIs were also analyzed. RESULTS: Among the 118,258 patients prescribed OAAs in 2014, approximately 59% were middle-aged, and approximately half were diagnosed with breast cancer. The number of comorbidities increased over time, and majority were diagnosed with gastrointestinal disorders, hyperlipidemia, and psychonervous disorders. The PDDIs due to protein kinase inhibitors (PKIs) with gastrointestinal/metabolic and neurological drugs increased 3.1- and 4.9-fold, respectively, over the 5 years, and 24.0% of the PDDIs fell into category X. Tamoxifen, the most commonly prescribed OAAs, caused the PDDIs with antidepressants through QTc prolongation or pharmacokinetic interaction. The PKIs prescription, cancer type like breast or hematologic cancer, and number of comorbidities or co-prescribing drugs were independently associated with the occurrence of PDDIs. CONCLUSIONS: The risk of PDDIs in patients receiving OAAs increases, particularly with the concomitant use of PKIs with gastrointestinal or psychiatric drugs and endocrine agents with antidepressants. Considering the potential risk of chronic concomitant use of these drug classes in outpatients, healthcare professionals should be made aware of the potential interactions.

Network analysis of drug-related problems in hospitalized patients with hematologic malignancies.

PURPOSE: Network analysis was conducted to systematically analyze the relationship between causative drugs and types of drug-related problems (DRPs) in hospitalized patients with hematologic malignancies. METHODS: A total of 1187 DRPs identified in hematology wards between 2013 and 2015 were analyzed. DRPs were classified into 11 sub-domains for problems and 35 sub-domains for causes according to Pharmaceutical Care Network Europe classification. Causative drugs were classified by Anatomical Therapeutic Chemical code. Network analytic tool was used to represent the relationship between drugs, causes, and problems. In-degree centrality (CD-in) was calculated to identify major causes of DRPs. RESULTS: The following drugs accounted for more than 5% of DRP, including antibacterials (J01, 26.5%), drugs for acid-related disorders (A02, 11.5%), antiemetics (A04, 9.7%), antifungals (J02, 8.8%), and antineoplastic agents (L01, 7.0%). Inappropriate combinations (C1.3, CD-in of 161) of drugs for acid-related disorders, antifungals, and antineoplastic agents were major causes of DRPs and induced non-optimal effects of drug treatment (P1.2). Inappropriate dose adjustments (C3.6, CD-in of 151) of antibacterials lowered effects (P1.2) and increased side effects (P2.1). Missing necessary synergistic or preventive drugs, especially antiemetics, (C1.8, CD-in of 54) resulted in untreated indication (P1.4). CONCLUSIONS: DRPs were mainly related to medications for supportive care. More attention should be paid to interactions of drugs used for acid-related disorders, dose adjustment of antibacterials, and omission of antiemetics in hospitalized patients with hematologic malignancy.

Construction of a database for published phase II/III drug intervention clinical trials for the period 2009-2014 comprising 2,326 records, 90 disease categories, and 939 drug entities.

OBJECTIVES: To construct a database of published clinical drug trials suitable for use 1) as a research tool in accessing clinical trial information and 2) in evidence-based decision-making by regulatory professionals, clinical research investigators, and medical practitioners. MATERIALS: Comprehensive information obtained from a search of design elements and results of clinical trials in peer reviewed journals using PubMed (http://www.ncbi.nlm.ih.gov/pubmed). METHOD: The methodology to develop a structured database was devised by a panel composed of experts in medical, pharmaceutical, information technology, and members of Ministry of Food and Drug Safety (MFDS) using a step by step approach. A double-sided system consisting of user mode and manager mode served as the framework for the database; elements of interest from each trial were entered via secure manager mode enabling the input information to be accessed in a user-friendly manner (user mode). Information regarding methodology used and results of drug treatment were extracted as detail elements of each data set and then inputted into the web-based database system. RESULTS: Comprehensive information comprising 2,326 clinical trial records, 90 disease states, and 939 drugs entities and concerning study objectives, background, methods used, results, and conclusion could be extracted from published information on phase II/III drug intervention clinical trials appearing in SCI journals within the last 10 years. The extracted data was successfully assembled into a clinical drug trial database with easy access suitable for use as a research tool. The clinically most important therapeutic categories, i.e., cancer, cardiovascular, respiratory, neurological, metabolic, urogenital, gastrointestinal, psychological, and infectious diseases were covered by the database. Names of test and control drugs, details on primary and secondary outcomes and indexed keywords could also be retrieved and built into the database. The construction used in the database enables the user to sort and download targeted information as a Microsoft Excel spreadsheet. CONCLUSION: Because of the comprehensive and standardized nature of the clinical drug trial database and its ease of access it should serve as valuable information repository and research tool for accessing clinical trial information and making evidence-based decisions by regulatory professionals, clinical research investigators, and medical practitioners.

Dissecting the roles of the histone chaperones reveals the evolutionary conserved mechanism of transcription-coupled deposition of H3.3.

The mammalian genome encodes multiple variants of histone H3 including H3.1/H3.2 and H3.3. In contrast to H3.1/H3.2, H3.3 is enriched in the actively transcribed euchromatin and the telomeric heterochromatins. However, the mechanism for H3.3 to incorporate into the different domains of chromatin is not known. Here, taking the advantage of well-defined transcription analysis system of yeast, we attempted to understand the molecular mechanism of selective deposition of human H3.3 into actively transcribed genes. We show that there are systemic H3 substrate-selection mechanisms operating even in yeasts, which encode a single type of H3. Yeast HIR complex mediated H3-specific recognition specificity for deposition of H3.3 in the transcribed genes. A critical component of this process was the H3 A-IG code composed of amino acids 87, 89 and 90. The preference toward H3.3 was completely lost when HIR subunits were absent and partially suppressed by human HIRA. Asf1 allows the influx of H3, regardless of H3 type. We propose that H3.3 is introduced into the active euchromatin by targeting the recycling pathway that is mediated by HIRA (or HIR), and this H3-selection mechanism is highly conserved through the evolution. These results also uncover an unexpected role of RI chaperones in evolution of variant H3s.

Myogenic transcriptional activation of MyoD mediated by replication-independent histone deposition.

In mammals, the canonical histone H3 and the variant H3.3 are assembled into chromatin through replication-coupled and replication-independent (RI) histone deposition pathways, respectively, to play distinct roles in chromatin function. H3.3 is largely associated with transcriptionally active regions via the activity of RI histone chaperone, HIRA. However, the precise role of the RI pathway and HIRA in active transcription and the mechanisms by which H3.3 affects gene activity are not known. In this study, we show that HIRA is an essential factor for muscle development by establishing MyoD activation in myotubes. HIRA and Asf1a, but not CHD1 or Asf1b, mediate H3.3 incorporation in the promoter and the critical upstream regulatory regions of the MyoD gene. HIRA and H3.3 are required for epigenetic transition into the more permissive chromatin structure for polymerase II recruitment to the promoter, regardless of transcription-associated covalent modification of histones. Our results suggest distinct epigenetic management of the master regulator with RI pathway components for cellular differentiation.

Utilizing temporal pattern of adverse event reports to identify potential late-onset adverse events.

OBJECTIVES: Through the use of FDA adverse event reporting system (FAERS) dataset, this study analyzes the pattern of time-to-event (TTE) for drugs and adverse events, and suggest ways to identify candidate late-onset events for monitoring. METHODS: The duration between administration date of the drug and the onset of adverse events was explored with using FAERS data from 2012-2021. The fold change of proportional reporting ratios or reporting odds ratios were calculated to identify enriched events in the later period and to suggest the late-onset events for further monitoring. To compare the findings, we used the claims database of the Korean National Health Insurance Service (NHIS). RESULTS: A total of 1,426,781 reports were included. The median TTE was 10 days (interquartile range [IQR]: 0-98 days), with 11.5% (n = 164,093) reporting events that occurred at least one year after administration. TTE and fold change analysis captured historical cases of late-onset events, while generating an additional less-explored list of events. The results for tumor necrosis factor (TNF) inhibitors were compared using the NHIS dataset. CONCLUSION: Our study provides a comprehensive analysis of the FAERS dataset, focusing on TTE data. Periodic summarization of reports would be helpful in monitoring the late-onset events.

Adverse events associated with SARS-CoV-2 neutralizing monoclonal antibodies using the FDA adverse event reporting system database.

The purpose of this study was to analyze the important medical events (IMEs) of anti-severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) monoclonal antibodies using the reports from the United States Food and Drug Administration (US FDA) adverse event reporting system (FAERS) and to detect safety signals. In this study, data from the FAERS from January 2020 to December 2022 were used to investigate signals associated with five monoclonal antibody products (bamlanivimab, bamlanivimab/etesevimab, bebtelovimab, casirivimab/imdevimab, sotrovimab) in coronavirus disease 2019 (COVID-19) patients and one monoclonal antibody product (tixagevimab/cilgavimab) in patients wherein COVID-19 vaccination was not recommended. Disproportionality analyses were conducted using the reporting odds ratio, and an information component to identify safety signals. There were 17,937,860 drug AE reports associated with all drugs in the FAERS documented during research period. Among them, 42,642 were AE reports associated with anti-SARS-CoV-2 monoclonal antibodies. The SOCs including respiratory, thoracic and mediastinal, and vascular disorders were frequently reported for all the six products. The three most commonly detected IMEs were hypoxia, COVID-19 pneumonia, and anaphylactic reaction due to SARS-CoV-2 neutralizing antibodies. Even though the purposes of use were different, the types of signals between drugs were similar. Careful monitoring of these AEs should be considered for certain COVID-19 patients, at risk, when they are treated with monoclonal antibody products.

Comparison of active tuberculosis occurrence associated with Janus kinase inhibitors and biological DMARDs in rheumatoid arthritis.

OBJECTIVES: This study aimed to evaluate the risk of tuberculosis associated with the use of Janus kinase (JAK) inhibitors or biological disease-modifying antirheumatic drugs (bDMARDs) in patients diagnosed with rheumatoid arthritis (RA) in South Korea. METHODS: In this nationwide matched-cohort study, we retrospectively identified adult patients with new-onset RA from the National Health Insurance Service database who were prescribed bDMARDs or JAK inhibitors and recently underwent latent tuberculosis infection (LTBI) screening during 2012‒2021, and followed them up until the end of 2022 for the development of active tuberculosis. HRs were estimated using Cox proportional hazards regression in a propensity score-matched cohort. RESULTS: Among 16 760 matched patients with RA (3352 JAK inhibitor users and 13 408 bDMARD users), 18.8% received tuberculosis preventive therapy for LTBI. Overall, JAK inhibitor users had a significantly lower risk of tuberculosis than bDMARD users (HR (95% CI)=0.37 (0.22 to 0.62)). Among the patients treated for LTBI, patients with low treatment adherence had a significantly higher risk than those without LTBI (HR (95% CI)=2.78 (1.74 to 4.44)). Patients without LTBI and using JAK inhibitors had a significantly lower risk of tuberculosis across all ages and sexes compared with bDMARD users. CONCLUSION: Patients with RA using JAK inhibitors have a significantly lower risk of active tuberculosis than bDMARD users in South Korea; however, patients with RA having LTBI are equally at risk regardless of the treatment received (JAK inhibitor vs bDMARD). Therefore, vigilant tuberculosis monitoring, especially in patients with low adherence to tuberculosis preventive therapy, is essential.

Distinct roles of two ceramide synthases, CaLag1p and CaLac1p, in the morphogenesis of Candida albicans.

Lag1p and Lac1p catalyse ceramide synthesis in Saccharomyces cerevisiae. This study shows that Lag1 family proteins are generally required for polarized growth in hemiascomycetous yeast. However, in contrast to S. cerevisiae where these proteins are functionally redundant, C. albicans Lag1p (CaLag1p) and Lac1p (CaLac1p) are functionally distinct. Lack of CaLag1p, but not CaLac1p, caused severe defects in the growth and hyphal morphogenesis of C. albicans. Deletion of CaLAG1 decreased expression of the hypha-specific HWP1 and ECE1 genes. Moreover, overexpression of CaLAG1 induced pseudohyphal growth in this organism under non-hypha-inducing conditions, suggesting that CaLag1p is necessary for relaying signals to induce hypha-specific gene expression. Analysis of ceramide and sphingolipid composition revealed that CaLag1p predominantly synthesizes ceramides with C24:0/C26:0 fatty acid moieties, which are involved in generating inositol-containing sphingolipids, whereas CaLac1p produces ceramides with C18:0 fatty acid moieties, which are precursors for glucosylsphingolipids. Thus, our study demonstrates that CaLag1p and CaLac1p have distinct substrate specificities and physiological roles in C. albicans.

Cardiovascular risk of Janus kinase inhibitors compared with biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis without underlying cardiovascular diseases: a nationwide cohort study.

Objectives: Despite the ethnic differences in cardiovascular (CV) risks and recent increase in the prescription of Janus kinase (JAK) inhibitors, limited evidence is available for their CV outcomes in Asian patients with rheumatoid arthritis (RA). We aimed to compare the major adverse CV events (MACEs) of JAK inhibitors to those of biologic disease-modifying antirheumatic drugs (bDMARDs) in Korean patients with RA without baseline CV disease (CVD). Methods: In a nationwide retrospective cohort study, patients newly diagnosed with RA without a history of CVD between 2013 and 2018 were identified using the National Health Insurance Service database. The cohort was followed up until the end of 2019 for the development of MACEs. Hazard ratios (HRs) for MACEs such as myocardial infarction, stroke, coronary revascularization, or all-cause death, were estimated using Cox proportional hazard regression in a propensity score-matched cohort. Results: In total, 4,230 matched patients with RA were included (846 JAK inhibitor users and 3,384 bDMARD users). The crude incidence rate (95% confidence intervals, CI) per 100 patient-years for MACEs was 0.83 (0.31-1.81) and 0.74 (0.53-1.02) in the JAK inhibitor and bDMARD groups, respectively. The risk of MACEs was not significantly different between JAK inhibitor and bDMARD users with an adjusted HR (95% CI) of 1.28 (0.53-3.11). There were no significant differences in the risk of MACEs between JAK inhibitors and bDMARDs in each subgroup according to the types of bDMARDs, age, sex, Charlson comorbidity index score, and comorbidities. Conclusion: Compared to bDMARDs, JAK inhibitors were not associated with the occurrence of MACEs in Korean patients with RA without a history of CVD.

Performance of Cardiovascular Risk Prediction Models in Korean Patients With New-Onset Rheumatoid Arthritis: National Cohort Study.

BACKGROUND: This study aimed to compare the performance of established cardiovascular risk algorithms in Korean patients with new-onset rheumatoid arthritis. METHODS AND RESULTS: This retrospective cohort study identified patients newly diagnosed with rheumatoid arthritis without a history of cardiovascular diseases between 2013 and 2019 using the National Health Insurance Service database. The cohort was followed up until 2020 for the development of the first major adverse cardiovascular event. General cardiovascular risk prediction algorithms, such as the systematic coronary risk evaluation model, the Korean risk prediction model for atherosclerotic cardiovascular diseases, the American College of Cardiology/American Heart Association pooled equations, and the Framingham Risk Score, were used. The discrimination and calibration of cardiovascular risk prediction models were evaluated. Hazard ratios were estimated using Cox proportional hazards regression. A total of 611 patients among 24 889 patients experienced a major adverse cardiovascular event during follow-up. The median 10-year atherosclerotic cardiovascular diseases risk score was significantly higher in patients with major adverse cardiovascular events than those without. The C-statistics of risk algorithms ranged between 0.72 and 0.74. Compared with the low-risk group, the actual risk of developing major adverse cardiovascular events increased significantly in the intermediate- and high-risk groups for all algorithms. However, the risk predictions calculated from all algorithms overestimated the observed cardiovascular risk in the middle to high deciles, and only the systematic coronary risk evaluation algorithm showed comparable observed and predicted event rates in the low-intermediate deciles with the highest sensitivity. CONCLUSIONS: The systematic coronary risk evaluation model algorithm and the general risk prediction models discriminated patients with rheumatoid arthritis appropriately. However, overestimation should be considered when applying the cardiovascular risk prediction model in Korean patients.

Prognostic Significance of the Severity of Immune-Related Adverse Events in Advanced Cancer Patients Treated with PD-1/PD-L1 Inhibitors: A Real-World Data Analysis.

BACKGROUND: There is limited evidence regarding immune-related adverse events (irAEs) in Asian cancer patients treated with antibodies directed against programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1). OBJECTIVE: This study aimed to investigate the clinical patterns and prognostic significance of grade 1-2 and grade ≥ 3 irAEs by PD-1/PD-L1 inhibitors in cancer patients using real-world clinical data. PATIENTS AND METHODS: We conducted a retrospective study of cancer patients who received pembrolizumab, nivolumab, or atezolizumab at a tertiary hospital in South Korea. Incidence, time to onset, and grade 1-2 and grade ≥ 3 irAE risk factors were analyzed from medical records. The association of irAE severity with progression-free survival (PFS) and prognostic factors for PFS were evaluated. RESULTS: Among a total of 431 patients, irAEs occurred in 45.2%, and 9.5% were grade ≥ 3 irAEs. There were no significant differences in the median time to onset based on severity. Risk factors for the development of grade ≥ 3 irAEs were the presence of autoimmune disorders or diabetes mellitus. The median PFS was significantly different at 13.20, 9.00 and 4.17 months for the grade 1-2, grade ≥ 3, and no irAE groups, respectively. An increase in administration cycles was associated with a reduced risk of progression in patients with grade 1-2 and grade ≥ 3 irAEs. CONCLUSIONS: The development of grade ≥ 3 irAEs was affected by comorbidities and associated with improved PFS compared with those without irAEs. Our findings identified the real-world epidemiology, risk factors, and prognostic significance of irAEs, which may guide treatment decisions of PD-1/PD-L1 inhibitors.

Association of Tumor Necrosis Factor Inhibitors with the Risk of Nontuberculous Mycobacterial Infection in Patients with Rheumatoid Arthritis: A Nationwide Cohort Study.

Tumor necrosis factor inhibitors (TNFi) are proposed as a risk factor for nontuberculous mycobacteria (NTM) infection. Limited research investigates NTM infection risk in rheumatoid arthritis (RA) patients treated with TNFi compared to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), considering other concurrent or prior non-TNFi antirheumatic drugs. We aimed to evaluate the NTM infection risk associated with TNFi using a real-world database. Patients with RA treated with TNFi or csDMARDs between 2005 and 2016 were identified utilizing the Korean National Health Insurance Service database. To minimize potential bias, we aligned the initiation year of csDMARDs for both TNFi and csDMARD users and tracked them from their respective treatment start dates. The association of TNFi with NTM infection risk was estimated in a one-to-one matched cohort using a multivariable conditional Cox regression analysis. In the matched cohort (n = 4556), the incidence rates of NTM infection were 2.47 and 3.66 per 1000 person-year in TNFi and csDMARD users. Compared to csDMARDs, TNFi did not increase the risk of NTM infection (adjusted hazard ratio (aHR) 0.517 (95% confidence interval, 0.205-1.301)). The TNFi use in RA patients was not associated with an increased risk of NTM infection compared to csDMARDs. Nevertheless, monitoring during TNFi treatment is crucial.

The role of histone chaperones in osteoblastic differentiation of C2C12 myoblasts.

Cellular differentiation is a process in which the cells gain a more specialized shape, metabolism, and function. These cellular changes are accompanied by dynamic changes in gene expression programs. In most cases, DNA methylation, histone modification, and variant histones drive the epigenetic transition that reprograms the gene expression. Histone chaperones, HIRA and Asf1a, have a role for cellular differentiation by deposition of one of variant histones, H3.3, during myogenesis of murine C2C12 cells. In this study, we accessed the roles of histone chaperones and histone H3.3 in osteoblastic conversion of C2C12 myoblasts and compared their roles with those for myogenic differentiation. The unbiased analysis of the expression pattern of histone chaperones and variant histones proposed their uncommon contribution to each pathway. HIRA and Asf1a decreased to ∼50% and further diminished during differentiation into osteoblasts, while they were maintained during differentiation into myotubes. HIRA, Asf1a, and H3.3 were indispensable for expression of cell type-specific genes during conversion into osteoblasts or myotubes. RNA interference analysis indicated that histone chaperones and H3.3 were required for early steps of osteoblastic differentiation. Our results suggest that histone chaperones and variant histones might be differentially required for the distinct phases of differentiation pathway.

Development of chitosan-based ondansetron buccal delivery system for the treatment of emesis.

BACKGROUND: For the buccal drug delivery, chitosan (CS) can be used to improve drug absorption and reduce application frequency and drug amount. The aim of this study is to develop and evaluate mucoadhesive ondansetron buccal films for the treatment of emesis using CS as a mucoadhesive polymer. METHODS: The film prepared by solvent casting method was comprised of ondansetron (approximately 65 µg)-loaded mucoadhesive gels containing 1, 2 or 3% CS and impermeable backing layer. Rheological property of the gels, physiochemical properties of the films (weight, thickness, drug content, swelling ratio, adhesion time and mucoadhesive force) and in vitro ondansetron release profile from the films were determined to evaluate the formulation. The films containing 3% CS (diameter: 0.5 cm; thickness: 170 µm) was selected as the novel formulation, and were used for the in vivo study. Comparative pharmacokinetic studies of ondansetron with this film and oral solution were performed at the same dose in hamsters. RESULTS: The mean values of T(max) and C(max) of the film and oral solution were similar. However, the half-life, mean residence time and AUC(0-24 h) of the film were about 1.7, 1.4 and 2.0-fold higher than those of the oral solution, respectively. The film showed enhanced bioavailability and prolonged efficacy compared to the oral solution. CONCLUSIONS: The mucoadhesive ondansetron buccal film may be a potential alternative to the marketed oral formulation, parenterals and solid suppositories with better patient compliance and higher bioavailability for the treatment of emesis.

Comparison of Online Patient Reviews and National Pharmacovigilance Data for Tramadol-Related Adverse Events: Comparative Observational Study.

BACKGROUND: Tramadol is known to cause fewer adverse events (AEs) than other opioids. However, recent research has raised concerns about various safety issues. OBJECTIVE: We aimed to explore these new AEs related to tramadol using social media and conventional pharmacovigilance data. METHODS: This study used 2 data sets, 1 from patients' drug reviews on WebMD (January 2007 to January 2021) and 1 from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS; January 2016 to December 2020). We analyzed 2062 and 29,350 patient reports from WebMD and FAERS, respectively. Patient posts on WebMD were manually assigned the preferred terms of the Medical Dictionary for Regulatory Activities. To analyze AEs from FAERS, a disproportionality analysis was performed with 3 measures: proportional reporting ratio, reporting odds ratio, and information component. RESULTS: From the 869 AEs reported, we identified 125 new signals related to tramadol use not listed on the drug label that satisfied all 3 signal detection criteria. In addition, 20 serious AEs were selected from new signals. Among new serious AEs, vascular disorders had the largest signal detection criteria value. Based on the disproportionality analysis and patients' symptom descriptions, tramadol-induced pain might also be an unexpected AE. CONCLUSIONS: This study detected several novel signals related to tramadol use, suggesting newly identified possible AEs. Additionally, this study indicates that unexpected AEs can be detected using social media analysis alongside traditional pharmacovigilance data.