PCSK9 Inhibitors and Infection-Related Adverse Events: A Pharmacovigilance Study Using the World Health Organization VigiBase.

AIMS: Protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are novel lipid-lowering agents used in patients with cardiovascular disease. Despite reassuring safety data from pivotal trials, increasing evidence from real-world studies suggests that PCSK9i increase the risk of bacterial and viral infections. Therefore, this study aimed to identify signals of infection-related adverse events (AEs) associated with PCSK9i. METHODS: We performed an observational pharmacovigilance study using the World Health Organization's VigiBase, recorded up to December 2022. We included individual case safety reports (ICSRs) of PCSK9 inhibitors, alirocumab and evolocumab, and compared them with those of other drugs. Infection-related ICSRs were retrieved from the Medical Dictionary for Regulatory Activities System Organ Class 'infections and infestations.' RESULTS: Among 114,293 reports (258,099 drug-AE pairs) related to PCSK9 inhibitors, 54% included female patients, 41% included patients aged ≥65 years, and 82% included patients who received evolocumab. Additionally, beyond AEs recognized by regulatory authorities, organ infections such as influenza (reporting odds ratio [ROR] 2.89, 95% confidence interval [CI] 2.74-3.05), gastric infections (ROR 2.47, 95% CI 1.63-3.75), and kidney infections (ROR 1.36, 95% CI 1.06-1.73) were observed. Sensitivity analysis indicated a heightened risk of infection-related AEs associated with PCSK9i regardless of the specific drug type. CONCLUSIONS: In addition to the labelled respiratory infections, six infection-related symptoms in the gastrointestinal, urinary, and renal organs were identified. Our findings support the need for systematic surveillance of infections among PCSK9i users.

Age-related off-label drug prescribing in pediatric patients in South Korea and consistency of labeling compared to the United States, Europe, and Japan.

Insufficient labeling information regarding the appropriate age for prescribing drugs to the pediatric population is challenging. This study aimed to analyze the off-label prescription of age-related drugs for pediatric patients using claims data from South Korea and to assess the consistency of the approved age in South Korea, the United States, Europe, and Japan. In 2020, 1004 unique drugs were prescribed to the pediatric population in South Korea. We found that 641 drugs (63.8%, p < 0.0001) were related to off-label prescriptions for age-related use at least once, and the total number of off-label prescriptions was 2,236,669 (62.2%, p < 0.0001). Chlorpheniramine (28%) was the most frequently prescribed drug for pediatric patients with an age-related off-label, followed by budesonide (9%) and epinephrine (9%). The degree of agreement in the approved age range for 641 off-label drugs across countries was assessed using the overall kappa coefficient. We observed slight agreement in labeling across all countries (κ: 0.16, 95% confidence interval [CI]: 0.14-0.18). The highest degree of agreement was observed between the United States and Europe (0.41, 0.37-0.45) due to pediatric-population-specific legislation. South Korea showed the lowest degree of agreement with the United States and Europe (0.10, 0.06-0.14). The United States, Europe, and Japan showed fair agreement (0.23, 0.21-0.26). However, the degree of agreement between South Korea, the United States, and Japan (0.09, 0.06-0.11) and South Korea, Europe, and Japan (0.08, 0.05-0.10) was low. This study highlights the need for South Korean regulatory agencies to consider introducing pediatric legislation to prescribe evidence-based drugs for safe and effective use.

Adverse Pregnancy and Child Outcomes in Oral Retinoid-Exposed Pregnancies: A Nationwide Population-Based Study.

BACKGROUND: Oral retinoids are used to treat various dermatological conditions, and their use is increasing in women of childbearing age. However, there is limited knowledge on the incidence of adverse outcomes after retinoid exposure during pregnancy. We aimed to evaluate the risk of adverse outcomes associated with oral retinoid exposure during pregnancy. METHODS: We conducted a retrospective cohort study using the NHIS mother-child linked healthcare database in South Korea. We included all women who gave live birth from April 1, 2009 to December 31, 2020 and their children. The exposure was defined as having ≥ 1 prescription of isotretinoin, alitretinoin, and acitretin from one month before pregnancy to the delivery. The outcomes of interest were adverse child outcomes including major congenital malformations, low birth weight, and neurodevelopmental disorders (autism spectrum disorder and intellectual disorder), and adverse pregnancy outcomes including gestational diabetes mellitus, preeclampsia, and postpartum hemorrhage. Propensity score-based matching weights were used to control for various potential confounders. For congenital malformation, low birth weight, and adverse pregnancy outcomes, we calculated relative risk (RR) with 95% confidence interval (CI) using a generalized linear model and for neurodevelopmental disorders, we estimated hazard ratio (HR) with 95% CI using the Cox proportional hazard model. RESULTS: Of 3,894,184 pregnancies, we identified 720 pregnancies (0.02%) as the oral retinoid-exposed group. The incidence of major congenital malformation was 400.6 per 10,000 births for oral retinoid-exposed group and 357.9 per 10,000 births for unexposed group and the weighted RR was 1.10 (95% CI, 0.65-1.85) in oral retinoid-exposed group compared with unexposed group. The neurodevelopmental disorder showed a potential increased risk, with the weighted HR of 1.63 (95% CI, 0.60-4.41) for autism spectrum disorder and 1.71 (95% CI, 0.60-4.93) for the intellectual disorder, although it did not reach statistical significance. For low birth weight and adverse pregnancy outcomes, no association was observed with oral retinoid exposure during pregnancy. CONCLUSION: This study found no significantly increased risk of congenital malformations, autism spectrum disorders, and intellectual disability associated with oral retinoid exposure during pregnancy; however, given the limitations such as including only the live births and increased point estimate, potential risk cannot be fully excluded.

A real-world pharmacovigilance study on cardiovascular adverse events of tisagenlecleucel using machine learning approach.

Chimeric antigen receptor T-cell (CAR-T) therapies are a paradigm-shifting therapeutic in patients with hematological malignancies. However, some concerns remain that they may cause serious cardiovascular adverse events (AEs), for which data are scarce. In this study, gradient boosting machine algorithm-based model was fitted to identify safety signals of serious cardiovascular AEs reported for tisagenlecleucel in the World Health Organization Vigibase up until February 2024. Input dataset, comprised of positive and negative controls of tisagenlecleucel based on its labeling information and literature search, was used to train the model. Then, we implemented the model to calculate the predicted probability of serious cardiovascular AEs defined by preferred terms included in the important medical event list from European Medicine Agency. There were 467 distinct AEs from 3,280 safety cases reports for tisagenlecleucel, of which 363 (77.7%) were classified as positive controls, 66 (14.2%) as negative controls, and 37 (7.9%) as unknown AEs. The prediction model had area under the receiver operating characteristic curve of 0.76 in the test dataset application. Of the unknown AEs, six cardiovascular AEs were predicted as the safety signals: bradycardia (predicted probability 0.99), pleural effusion (0.98), pulseless electrical activity (0.89), cardiotoxicity (0.83), cardio-respiratory arrest (0.69), and acute myocardial infarction (0.58). Our findings underscore vigilant monitoring of acute cardiotoxicities with tisagenlecleucel therapy.

PLD1 is a key player in cancer stemness and chemoresistance: Therapeutic targeting of cross-talk between the PI3K/Akt and Wnt/ß-catenin pathways.

The development of chemoresistance is a major challenge in the treatment of several types of cancers in clinical settings. Stemness and chemoresistance are the chief causes of poor clinical outcomes. In this context, we hypothesized that understanding the signaling pathways responsible for chemoresistance in cancers is crucial for the development of novel targeted therapies to overcome drug resistance. Among the aberrantly activated pathways, the PI3K-Akt/Wnt/ß-catenin signaling pathway is clinically implicated in malignancies such as colorectal cancer (CRC) and glioblastoma multiforme (GBM). Aberrant dysregulation of phospholipase D (PLD) has been implicated in several malignancies, and oncogenic activation of this pathway facilitates tumor proliferation, stemness, and chemoresistance. Crosstalk involving the PLD and Wnt/ß-catenin pathways promotes the progression of CRC and GBM and reduces the sensitivity of cancer cells to standard therapies. Notably, both pathways are tightly regulated and connected at multiple levels by upstream and downstream effectors. Thus, gaining deeper insights into the interactions between these pathways would help researchers discover unique therapeutic targets for the management of drug-resistant cancers. Here, we review the molecular mechanisms by which PLD signaling stimulates stemness and chemoresistance in CRC and GBM. Thus, the current review aims to address the importance of PLD as a central player coordinating cross-talk between the PI3K/Akt and Wnt/ß-catenin pathways and proposes the possibility of targeting these pathways to improve cancer therapy and overcome drug resistance.

Cardiovascular Safety of COVID-19 Vaccination in Patients With Cancer: A Self-Controlled Case Series Study in Korea.

BACKGROUND: Cancer patients have an increased risk of cardiovascular outcomes and are susceptible to coronavirus disease 2019 (COVID-19) infection. We aimed to assess the cardiovascular safety of COVID-19 vaccination for cancer patients in South Korea. METHODS: We conducted a self-controlled case series study using the K-COV-N cohort (2018-2021). Patients with cancer aged 12 years or older who experienced cardiovascular outcomes were identified. Cardiovascular outcomes were defined as myocardial infarction, stroke, venous thromboembolism (VTE), myocarditis, or pericarditis, and the risk period was 0-28 days after receiving each dose of COVID-19 vaccines. A conditional Poisson regression model was used to calculate the incidence rate ratio (IRR) with 95% confidence interval (CI). RESULTS: Among 318,105 patients with cancer, 4,754 patients with cardiovascular outcomes were included. The overall cardiovascular risk was not increased (adjusted IRR, 0.99 [95% CI, 0.90-1.08]) during the whole risk period. The adjusted IRRs of total cardiovascular outcomes during the whole risk period according to the vaccine type were 1.07 (95% CI, 0.95-1.21) in the mRNA vaccine subgroup, 0.99 (95% CI, 0.83-1.19) in the ChAdOx1 nCoV-19 vaccine subgroup, and 0.86 (95% CI, 0.68-1.10) in the mix-matched vaccination subgroup. However, in the analysis of individual outcome, the adjusted IRR of myocarditis was increased to 11.71 (95% CI, 5.88-23.35) during the whole risk period. In contrast, no increased risk was observed for other outcomes, such as myocardial infarction, stroke, VTE, and pericarditis. CONCLUSION: For cancer patients, COVID-19 vaccination demonstrated an overall safe profile in terms of cardiovascular outcomes. However, caution is required as an increased risk of myocarditis following COVID-19 vaccination was observed in this study.

Lazertinib versus Platinum-Based Chemotherapy with Epidermal Growth Factor Receptor (EGFR)-Positive Non-Small-Cell Lung Cancer after Failing EGFR-Tyrosine Kinase Inhibitor: A Real-World External Comparator Study.

BACKGROUND: Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M mutation in non-small-cell lung cancer (NSCLC) patients. No previous studies have compared lazertinib to platinum-based chemotherapy. We have compared lazertinib with platinum-based chemotherapy in EGFR-mutated NSCLC patients after previous EGFR-TKI therapy. METHODS: We retrospectively compared 200 patients from LASER201, LASER301, and LASER-PMS studies to 334 patients who were treated with platinum-based chemotherapy after previous EGFR-TKI from the Samsung Medical Center. After propensity score matching (PSM), we selected 156 patients from each group. The primary outcome was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and time to treatment discontinuation (TTD) as secondary outcomes. RESULTS: The median follow-up of PFS was 15.61 months in the lazertinib group and 21.67 months in the external control group. The PFS was significantly longer in patients who were treated with lazertinib than those treated with platinum-based chemotherapy (10.97 months vs. 5.10 months; adjusted hazard ratio (HR) 0.40; 95% confidence interval (CI), 0.29-0.55; p < 0.01) after PSM. Lazertinib showed superior OS (32.23 months vs. 18.73 months; adjusted HR 0.45; 95% CI, 0.29-0.69; p < 0.001), ORR (64.1% vs. 47.4%), and TTD (11.66 months vs. 6.73 months; adjusted HR 0.54; 95% CI, 0.39-0.75; p < 0.001) compared to platinum-based chemotherapy. CONCLUSION: Based on this retrospective, external control study, lazertinib has demonstrated significantly better efficacy compared with platinum-based chemotherapy. The external controls provide important context to evaluate efficacy in single-arm studies.

Association between exposure to antibiotics during pregnancy or early infancy and risk of autism spectrum disorder, intellectual disorder, language disorder, and epilepsy in children: population based cohort study.

OBJECTIVE: To evaluate the association between antibiotic use during pregnancy or early infancy and the risk of neurodevelopmental disorders in children. DESIGN: Nationwide population based cohort study and sibling analysis. SETTING: Korea's National Health Insurance Service mother-child linked database, 2008-21. PARTICIPANTS: All children live born between 2009 and 2020, followed up until 2021 to compare those with and without antibiotic exposure during pregnancy or early infancy (first six months of life). MAIN OUTCOMES MEASURES: Autism spectrum disorder, intellectual disorder, language disorder, and epilepsy in children. After 1:1 propensity score matching based on many potential confounders, hazard ratios with 95% confidence interval were estimated using Cox proportional hazard models. A sibling analysis additionally accounted for unmeasured familial factors. RESULTS: After propensity score matching, 1 961 744 children were identified for the pregnancy analysis and 1 609 774 children were identified for the early infancy analysis. Although antibiotic exposure during pregnancy was associated with increased risks of all four neurodevelopmental disorders in the overall cohort, these estimates were attenuated towards the null in the sibling analyses (hazard ratio for autism spectrum disorder 1.06, 95% confidence interval 1.01 to 1.12; intellectual disorder 1.00, 0.93 to 1.07; language disorder 1.05, 1.02 to 1.09; and epilepsy 1.03, 0.98 to 1.08). Likewise, no association was observed between antibiotic exposure during early infancy and autism spectrum disorder (hazard ratio 1.00, 0.96 to 1.03), intellectual disorder (1.07, 0.98 to 1.15), and language disorder (1.04, 1.00 to 1.08) in the sibling analyses; however, a small increased risk of epilepsy was observed (1.13, 1.09 to 1.18). The results generally remained consistent across several subgroup and sensitivity analyses, except for slightly elevated risks observed among children who used antibiotics during very early life and those who used antibiotics for more than 15 days. CONCLUSIONS: In this large cohort study, antibiotic exposure during pregnancy or early infancy was not associated with an increased risk of autism spectrum disorder, intellectual disorder, or language disorder in children. However, elevated risks were observed in several subgroups such as children using antibiotics during very early life and those with long term antibiotic use, which warrants attention and further investigation. Moreover, antibiotic use during infancy was modestly associated with epilepsy, even after control for indications and familial factors. When prescribing antibiotics to pregnant women and infants, clinicians should carefully balance the benefits of use against potential risks.

Predictors, mortality, and health outcomes of intensive phase non-adherence to a regimen in patients with drug-susceptible tuberculosis: a nationwide linkage database.

OBJECTIVES: The clinical importance of adhering to the regimen in tuberculosis patients has been widely investigated, but most studies were conducted in controlled settings and in limited populations. We aimed to measure the level of real-world adherence during intensive phase and investigate the predictors and the risk of mortality and health outcomes of intensive phase non-adherence in tuberculosis patients. STUDY DESIGN: We conducted a nationwide cohort study by linking the Korean National Tuberculosis Surveillance System and the National Health Information Database. METHODS: We included all incident drug-susceptible tuberculosis patients who initiated the regimens recommended by the World Health Organization from 2013 to 2018. Adherence was measured using the proportion of days covered (poor [<50%], moderate [50%-79%], and high [≥80%]). We used logistic regression model to assess predictors and the Cox proportional hazard model to evaluate the risk of mortality and health outcomes with intensive phase non-adherence. RESULTS: Of 46,818 patients, there were 8% and 11% with poor and moderate adherent groups, respectively. Age ≥45 years, insulin use, and history of renal failure were predictors of non-adherence. Compared with high adherent group, poor and moderate adherent groups were associated with a substantial risk of mortality (poor: hazard ratio, 2.14 [95% confidence interval, 1.95-2.34]; moderate: 1.76 [1.62-1.92]). Similar trends were observed for health outcomes. Stratified analyses showed a higher risk of mortality in patients with medical aid, low income, and history of renal failure, systematic corticosteroids, and immunomodulators. CONCLUSIONS: Non-adherence during intensive phase increased mortality risk by twofold, underscoring targeted intervention for high-risk population, including advanced diabetes, and immunocompromised patients.

Neurological and immunological adverse events after pneumococcal conjugate vaccine in children using national immunization programme registry data.

BACKGROUND: Despite the general consensus on the safety of pneumococcal conjugate vaccine (PCV), safety concerns unveiled during post-licensure surveillance need to be addressed. We investigated whether there is a transient increased risk following a three-dose series of pneumococcal conjugate vaccine (PCV) administered at 2, 4 and 6 months of age. METHODS: This was a population-based cohort study using the Korea immunization registry data linked to nationwide administrative claims data. Self-controlled risk interval analysis was conducted for PCV recipients who had an outcome of interest within pre-defined risk and control intervals between 2018 and 2022. The outcomes were anaphylaxis, asthma, encephalopathy, febrile seizure, Kawasaki disease and thrombocytopenia. We used conditional Poisson regression model to estimate the incidence rate ratios (IRRs) and 95% confidence intervals (CIs) comparing the outcomes in the risk and control intervals. RESULTS: Of 1 114 096 PCV recipients, 8661 had outcomes either in the risk or control intervals. Their mean age at Dose 1 was 10.0 weeks, 58.3% were boys, and 85.3% received 13-valent PCV. PCV was not associated with an increased risk of any outcomes except for febrile seizure. There were 408 (56.0%) cases of febrile seizure in the risk interval, corresponding to an IRR of 1.27 (95% CI 1.10-1.47). CONCLUSIONS: It is reassuring to note that there was no increased risk of the potential safety concerns following PCV administration. Despite the transient increased risk of febrile seizure, absolute numbers of cases were small. Febrile seizure is generally self-limiting with a good prognosis, and should not discourage parents or caregivers from vaccinating their children.

Concomitant Use of Sodium-Glucose Cotransporter 2 Inhibitors and Overactive Bladder Drugs and the Risk of Urinary Tract Infection.

Concomitant use of sodium glucose cotransporter-2 inhibitors (SGLT-2i) and overactive bladder (OAB) drugs potentially poses a risk of urinary tract infections (UTIs) due to the urinary retention of highly concentrated glucose in the urine. Thus, this study aimed to investigate the risk of UTIs among patients who initiated SGLT-2i treatment while taking OAB drugs. This population-based cohort study included new-users of SGLT-2i or comparator antidiabetics (dipeptidyl peptidase-4 inhibitor (DPP-4i); glucagon-like peptide-1 receptor agonist (GLP-1RA)) with OAB drugs between 2014 and 2020 using claim data from Korea. Primary outcome was a composite UTI event composite end point comprising pyelonephritis, cystitis, and urethritis, using both inpatient and outpatient diagnoses. Propensity score fine stratification was used to adjust for potential confounding factors. Weighted hazard ratios (HR) were calculated using the Cox proportional hazards model. In the first cohort, 796 and 9,181 new-users of SGLT-2i and DPP-4i with OAB drugs were identified, respectively. This study found a similar risk of UTIs in concomitant users of SGLT-2i and DPP-4i (weighted HR 1.08, 95% confidence interval: 0.88-1.32) with OAB drugs. In the second cohort, 2,387 and 280 new-users of SGLT-2i and GLP-1RA with OAB drugs were identified, respectively. Initiation of SGLT-2i while on OAB treatment was not associated with increased risk of UTI (0.89, 0.50-1.60), compared with initiation of GLP-1RA. These results show that the concomitant use of SGLT-2i with OAB drugs was not associated with an increased risk of UTI compared with the concomitant use of DPP-4i or GLP-1RA with OAB drugs.

Cardiovascular, Neurological, and Immunological Adverse Events and the 23-Valent Pneumococcal Polysaccharide Vaccine.

Importance: Despite widespread immunization with the 23-valent pneumococcal polysaccharide vaccine (PPSV23), safety concerns remain owing to a lack of statistical power and largely outdated evidence. Objective: To evaluate the association between cardiovascular, neurological, and immunological adverse events and PPSV23 vaccination in older adults. Design, Setting, and Participants: This population-based cohort study using a self-controlled risk interval design used a large linked database created by linking the Korea Immunization Registry Information System and the National Health Information Database (2018 to 2021). Participants included patients aged 65 years or older with a history of PPSV23 vaccination and incident cardiovascular, neurological, or immunological events during the risk and control intervals. Data were analyzed from November 2022 to April 2023. Exposure: 23-valent pneumococcal polysaccharide vaccine. Main Outcomes and Measures: The occurrence of 1 among 6 cardiovascular events (myocardial infarction, atrial fibrillation, cardiomyopathy, heart failure, hypotension, and myocarditis or pericarditis), 2 neurological events (Bell palsy and Guillain-Barré syndrome), and 3 immunological events (sepsis, thrombocytopenia, and anaphylaxis) during the risk and control periods. The risk and control intervals were defined as 1 to 28 and 57 to 112 days after PPSV23 vaccination, respectively. Conditional Poisson regression was used to estimate the incidence rate ratio (IRR) with a 95% CI. Results: Altogether, 4355 of the 1 802 739 individuals who received PPSV23 vaccination and experienced at least 1 outcome event were included (mean [SD] age, 72.4 [8.2] years; 2272 male participants [52.1%]). For cardiovascular events, there were no significant associations for myocardial infarction (IRR, 0.96; 95% CI, 0.81-1.15), heart failure (IRR, 0.85; 95% CI, 0.70-1.04), and stroke (IRR, 0.92; 95% CI, 0.84-1.02). Similarly, no increased risks were observed for neurological and immunological outcomes: Bell palsy (IRR, 0.95; 95% CI, 0.72-1.26), Guillain-Barré syndrome (IRR, 0.27; 95% CI, 0.06-1.17), sepsis (IRR, 0.99; 95% CI, 0.74-1.32), and thrombocytopenia (IRR, 1.18; 95% CI, 0.60-2.35). Conclusions and Relevance: In this self-controlled risk interval study, there was no appreciable increase in risk for most cardiovascular, neurological, or immunological adverse events following PPSV23. The updated safety profile of PPSV23 provides supportive evidence for the establishment of immunization strategies for older adults.

Enhanced Photocatalytic Oxygen Evolution Using Copper-Coordinated Perylene Diimide Nanorod Assemblies.

A crystalline supramolecular photocatalyst is prepared through metal-induced self-assembly of perylene diimide with imidazole groups at the imide position (PDI-Hm). Exploiting the metal-coordination ability of imidazole, a crystalline assembly of copper-coordinated PDI-Hm (CuPDI-Hm) in a nanorod shape is prepared which displays an outstanding photocatalytic oxygen evolution rate of 25,900 µmol g-1 h-1 without additional co-catalysts. The imidazole-copper coordination, along with π-π stacking of PDI frameworks, guides the arrangement of PDI-Hm molecules to form highly crystalline assemblies. The coordination of copper also modulates the size of the CuPDI-Hm supramolecular assembly by regulating the nucleation and growth processes. Furthermore, the imidazole-copper coordination constructs the electric field within the PDI-Hm assembly, hindering the recombination of photo-induced charges to enhance the photoelectric/photocatalytic activity when compared to Cu-free PDI-Hm assemblies. Small CuPDI-Hm assembly exhibits higher photocatalytic activity due to their larger surface area and reduced light scattering. Together, the Cu-imidazole coordination presents a facile way for fabricating size-controlled crystalline PDI assemblies with built-in electric field enhancing photoelectric and photocatalytic activities substantially.

Real-Time Endomicroscopic Image Mosaicking with an EKF-based Sensor Fusion Approach.

This study presents a real-time sensor fusion framework based on the extended Kalman filter (EKF) for accurate and robust endomicroscopic image mosaicking. The sensor fusion framework incorporates an optical tracking system that can track 6-DOF pose of the imaging probe with high accuracy in real time in conjunction with 2D local image registration from image feature matching between two consecutive frames. We evaluated the performance of the real-time image mosaicking based on the sensor fusion compared with the image or tracker only approach. As a result, it could retain the microscopic level of image detail from the image-based approach and also achieve a robust image mosaic without any drift by using the accurate optical tracking system.

The Risk of Neuropsychiatric Adverse Events With Use of Leukotriene Receptor Antagonists in Patients With Asthma: Analysis of Korea's National Health Insurance Sharing Service Database.

BACKGROUND: Montelukast, a selective leukotriene receptor antagonist, is a commonly prescribed allergy medication but its potential association with neuropsychiatric adverse events is concerning. OBJECTIVE: To analyze Korea's National Health Insurance System claims records to identify the risk of neuropsychiatric adverse events in patients with asthma treated with montelukast. METHODS: This retrospective population-based study analyzed the National Health Insurance claims records of the entire Korean population between 2008 and 2015. We compared the risk of neuropsychiatric adverse events among patients with asthma using inhaled corticosteroids and/or long-acting ß2-agonists with montelukast or pranlukast and those not using leukotriene receptor antagonists (control group). RESULTS: There was no increased risk of the composite outcome of all measured neuropsychiatric adverse events in patients with asthma who were prescribed montelukast or pranlukast compared with those who were not. However, montelukast use was associated with an increased risk of hallucinations (inverse probability treatment weighting hazard ratio, 1.45; 95% CI, 1.07-1.96) and attention problems (inverse probability treatment weighting hazard ratio, 1.24; 95% CI, 1.01-1.52). Significant negative hazards for disorientation, anxiety, stress reactions, and somatic symptoms were observed in the montelukast group. When grouped by sex, the risk of hallucinations and attention problems was higher in men prescribed montelukast compared with the controls. CONCLUSIONS: We did not observe an increase in all neuropsychiatric adverse events in the leukotriene receptor antagonist-treated group; however, an increased risk of hallucinations and attention problems was observed in those taking montelukast, regardless of the medication administration period.

Rh-coordinated histidyl bolaamphiphile assembly: a catalyst for the isomerization of cis-stilbene and cis-alkene.

In this study, we present a colloidal assembly of histidyl bolaamphiphiles whose imidazoles coordinate with rhodium ions (HisC7[Rh]) to exhibit catalytic isomerization activity for cis-stilbene and cis-alkene molecules. The histidyl bolaamphiphiles self-assemble to form a soft scaffold that functions analogously to an apoenzyme. This scaffold exposes multiple histidyl imidazoles and carboxylates on its surface, to which rhodium ions bind, generating catalytically active sites. The Rh coordination with the biochemical functional groups was verified through comprehensive vibrational spectroscopy and calorimetry. The colloidal HisC7[Rh] demonstrated a significant catalytic effect on the isomerization of cis- to trans-stilbene under mild H2 conditions, resulting in 69% yield of trans-stilbene. In contrast, when Rh(cod)2BF4 was employed as a control catalyst, only the hydrogenated products of bibenzyl were obtained. These findings underscore the crucial role of histidyl motifs in exhibiting unique catalytic isomerization activity through the coordination with Rh. The catalytic activity of HisC7[Rh] is governed by several factors, such as rhodium content, solvent composition, temperature, and H2 pressure. Moreover, HisC7[Rh] displayed moderate isomerization activity towards not only stilbene but also unsaturated fatty acid isomers, highlighting its expansive potential as an isomerization catalyst.

Association of sodium-glucose cotransporter 2 inhibitors with post-discharge outcomes in patients with acute heart failure with type 2 diabetes: a cohort study.

BACKGROUND: Given the cumulative evidence on the effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on chronic heart failure, demand is emerging for further information on their effects in patients who are hospitalized for acute heart failure. However, there is still limited evidence about the class effect of SGLT2is on acute heart failure. We investigated whether initiating treatment with SGLT2is after an episode of acute heart failure reduces the risks of post-discharge heart failure readmission or cardiovascular mortality among patients with type 2 diabetes. METHODS: A retrospective cohort study was conducted in a cohort of patients with type 2 diabetes who hospitalized for heart failure, using Korean Health Insurance Review & Assessment database (2015-2020). The exposure was defined as initiation of SGLT2is during hospitalization or at discharge. We assessed hazards of post-discharge heart failure readmission and cardiovascular death at 1-year, and 30-, 60-, and 90-day from the date of discharge in the SGLT2is users and non-users. Cox proportional hazards models with propensity score-based inverse probability of treatment weighting were used to estimate hazard ratios and 95% confidence intervals. RESULTS: Among 56,343 patients with type 2 diabetes hospitalized for heart failure, 29,290 patients were included in the study cohort (mean [SD] age, 74.1 [10.8] years; 56.1% women); 818 patients (2.8%) were prescribed SGLT2is during index hospitalization or at discharge. Patients with a prescription for SGLT2i vs. those without prescription had lower rates of heart failure readmission or cardiovascular death at 1 year (22.4% vs. 25.3%; adjusted hazard ratio, 0.90 [95% confidence interval, 0.87-0.93]), and also at 30 days (7.0% vs. 7.7%%; 0.74 [0.69-0.79]). CONCLUSIONS: Among patients with type 2 diabetes, initiating SGLT2i treatment after an episode of acute heart failure was significantly associated with a reduced combined risk of heart failure readmission and cardiovascular mortality in a nationwide cohort reflecting routine clinical practice.

Risk of mortality and clinical outcomes associated with healthcare delay among patients with tuberculosis.

BACKGROUND: To eliminate tuberculosis (TB), World Health Organization (WHO) initiated "The End TB Strategy" with the goal of a 95% reduction in deaths. While many resources are contributed to eradicating TB, a substantial number of TB patients are still unlikely to receive timely treatment. Thus, we aimed to measure healthcare delay and its association with clinical outcomes from 2013 to 2018. METHODS: We conducted a retrospective cohort study using linked data of the National Tuberculosis Surveillance Registry and the health insurance claims data of South Korea. We included incident TB patients, and healthcare delay was defined as the period between the first medical visit with TB-related symptoms and the initiation of an anti-TB regimen. We described the distribution of healthcare delay, and the study population was classified into two groups with mean as a cutoff. The association between healthcare delay and clinical outcomes (all-cause mortality, pneumonia, progression to multi/extensively drug-resistant, intensive care unit admission, and mechanical ventilation use) was evaluated using the Cox proportional hazard model. Several stratified and sensitivity analyses were also conducted. RESULTS: Among 39,747 patients with pulmonary TB, mean healthcare delay was 42.3 days and delayed and non-delayed groups, classified by mean (or average), were 10,680 (26.9%) and 29,067 (73.1%), respectively. Healthcare delay was associated with an increased risk of all-cause mortality (HR 1.10, 95% CI 1.03-1.17), pneumonia (HR 1.13, 95% CI 1.09-1.18), and mechanical ventilation use (HR 1.15, 95% CI 1.01-1.32). We also observed the duration-response of healthcare delay. Stratified analyses showed patients with respiratory diseases were at higher risk, and consistent results were observed in sensitivity analyses. CONCLUSIONS: We observed a substantial number of patients experiencing healthcare delays, and it was associated with the deterioration of clinical outcomes. Our findings suggest that attention from authorities and healthcare professionals is needed to attenuate the preventable burden caused by TB through timely treatment.

Epidemiology of patients with asthma in Korea: Analysis of the NHISS database 2006-2015.

Background: There has been a concerning increase in the prevalence and socioeconomic burden of asthma in Korea. Korea's National Health Insurance System (NHIS) covers insurance payment and claims management for all Koreans. Using National Health Insurance Sharing Service (NHISS) claims data. This study aimed to investigate patterns of healthcare utilization and direct cost in patients with asthma over a 10-year period. Methods: In this retrospective population-based study, we examined NHISS claims records between July 2005 and June 2016 and investigated healthcare utilization among patients with asthma based on age group and severity of disease (non-severe asthma [NSA] and severe asthma [SA]). Results: From 2006 to 2015, the total number of patients with asthma in Korea steadily increased from 743 968 to 2 286 309, with a corresponding increase in prevalence from 1.62% to 4.74%. The proportion of patients with SA decreased from 3.16% in 2006 to 1.56% in 2015; the proportion was consistently higher in men than in women. In addition, patients with SA had a higher cost per outpatient visit than patients with NSA, and the number of outpatient visits per year increased. The inhaled corticosteroid (ICS) prescription rate among patients with asthma decreased from 22.9% in 2006 to 15.7% in 2015. Furthermore, for a period of 10 years, more than 40% of patients with SA have been prescribed short-acting ß-2 agonists (SABAs). Conclusions: Although patients with SA comprised a small proportion of patients with asthma, they incurred greater medical costs per person. The pharmaceutical prescription pattern indicated a lack of ICS-based prescriptions and frequent SABA prescriptions.

Comparative safety of bedaquiline and delamanid in patients with multidrug resistant tuberculosis: A nationwide retrospective cohort study.

BACKGROUND/PURPOSE(S): Bedaquiline and delamanid were recently approved for multidrug resistant tuberculosis (MDR-TB). Bedaquiline carries a black box warning of increased risk of death compared to the placebo arm, and there is a need to establish the risks of QT prolongation and hepatotoxicity for bedaquiline and delamanid. METHODS: We retrospectively analyzed data of MDR-TB patients retrieved from the South Korea national health insurance system database (2014-2020) to assess the risks of all-cause death, long QT-related cardiac event, and acute liver injury associated with bedaquiline or delamanid, compared with conventional regimen. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Stabilized inverse probability of treatment weighting based on propensity score was used to balance characteristics between the treatment groups. RESULTS: Of 1998 patients, 315 (15.8%) and 292 (14.6%) received bedaquiline and delamanid, respectively. Compared with conventional regimen, bedaquiline and delamanid did not increase risk of all-cause death at 24-month (HR 0.73 [95% CI, 0.42-1.27] and 0.89 [0.50-1.60], respectively). Bedaquiline-containing regimen increased risk of acute liver injury (1.76 [1.31-2.36]), while delamanid-containing regimen increased risk of long QT-related cardiac events (2.38 [1.05-3.57]) within 6 months of treatment. CONCLUSION: This study adds to the emerging evidence refuting the higher mortality rate observed in the bedaquiline trial population. Association between bedaquiline and acute liver injury needs careful interpretation considering for other background hepatotoxic anti-TB drugs. Our finding on delamanid and long QT-related cardiac events suggest careful risk-benefit assessment in patients with pre-existing cardiovascular disease.