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.

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.

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.

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.

Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes.

Seronegative autoimmune encephalitis is autoimmune encephalitis without any identifiable pathogenic antibody. Although it is a major subtype of autoimmune encephalitis, many unmet clinical needs exist in terms of clinical characteristics, treatments and prognosis. In this institutional cohort study, patients diagnosed with seronegative autoimmune encephalitis with available 2-year outcomes were analysed for the disease course, 2-year outcome prediction system, effect of immunotherapy, necessity of further immunotherapy at 6 or 12 months and pattern of brain atrophy. Seronegative autoimmune encephalitis was subcategorized into antibody-negative probable autoimmune encephalitis, autoimmune limbic encephalitis and acute disseminated encephalomyelitis. Poor 2-year outcome was defined by modified Rankin scale scores 3-6, and the 2-year serial data of Clinical Assessment Scales in Autoimmune Encephalitis score was used for longitudinal data analyses. A total of 147 patients were included. The frequency of achieving a good 2-year outcome (modified Rankin scale 0-2) was 56.5%. The antibody-negative probable autoimmune encephalitis subtype exhibited the poorest outcomes, although the baseline severity was similar among the subtypes. The RAPID score, consisting of five early usable clinical factors, refractory status epilepticus, age of onset ≥60 years, probable autoimmune encephalitis (antibody-negative probable autoimmune encephalitis subtype), infratentorial involvement and delay of immunotherapy ≥1 month, was associated with poorer 2-year outcomes. Any immunotherapy was associated with clinical improvement in the patients with low risk for poor 2-year outcomes (RAPID scores 0-1), and the combination immunotherapy of steroid, immunoglobulin, rituximab and tocilizumab was associated with better outcomes in the patients with high risk for poor 2-year outcomes (RAPID scores 2-5). In patients with persistent disease at 6 months, continuing immunotherapy was associated with more improvement, while the effect of continuing immunotherapy for more than 12 months was unclear. In the longitudinal analysis of MRI, the development of cerebellar atrophy indicated poor outcomes, while the absence of diffuse cerebral atrophy or medial temporal atrophy indicated the possibility of a good outcome. This study provides information about the clinical characteristics and courses, the effect of immunotherapy and its duration, and prognostic factors in seronegative autoimmune encephalitis.

Immeasurable Time Bias in Self-controlled Designs: Case-crossover, Case-time-control, and Case-case-time-control Analyses.

BACKGROUND: Impact of immeasurable time bias (IMTB) is yet to be examined in self-controlled designs. METHODS: We conducted case-crossover, case-time-control, and case-case-time-control analyses using Korea's healthcare database. Two empirical examples among elderly patients were used: 1) benzodiazepines-hip fracture; 2) benzodiazepines-mortality. For cases, the date of hip fracture diagnosis or death was defined as the index date, and the inherited date of their matched cases for controls or future cases. Exposure was assessed in the 1-30 day (hazard) and 61-90 day (control) windows preceding the index date. A non-missing exposure setting included in- and outpatient prescriptions and the pseudo-outpatient setting included only the outpatients. Conditional logistic regression was done to estimate odds ratios (ORs) with 95% confidence intervals (CIs), where the relative difference in OR among the two settings was calculated to quantify the IMTB. RESULTS: The IMTB had negligible impacts in the hip fracture example in the case-crossover (non-missing exposure setting OR 1.27; 95% CI, 1.12-1.44; pseudo-outpatient setting OR 1.21; 95% CI, 1.06-1.39; magnitude 0.05), case-time-control (OR 1.18; 95% CI, 0.98-1.44; OR 1.13; 95% CI, 0.92-1.38; 0.04, respectively), and case-case-time-control analyses (OR 0.99; 95% CI, 0.80-1.23; OR 0.94; 95% CI, 0.75-1.18; 0.05, respectively). In the mortality example, IMTB had significant impacts in the case-crossover (non-missing exposure setting OR 1.44; 95% CI, 1.36-1.52; pseudo-outpatient setting OR 0.72; 95% CI, 0.67-0.78; magnitude 1.00), case-time-control (OR 1.38; 95% CI, 1.26-1.51; OR 0.68; 95% CI, 0.61-0.76; 1.03, respectively), and case-case-time-control analyses (OR 1.27; 95% CI, 1.15-1.40; OR 0.62; 95% CI, 0.55-0.69; 1.05, respectively). CONCLUSION: Although IMTB had negligible impacts on the drug's effect on acute events, as these are unlikely to be accompanied with hospitalizations, it negatively biased the drug's effect on mortality, an outcome with prodromal phases, in the three self-controlled designs.

Trends of polypharmacy among older people in Asia, Australia and the United Kingdom: a multinational population-based study.

BACKGROUND: Polypharmacy among older people represents a global challenge due to its association with adverse drug events. The reported prevalence of polypharmacy varies widely across countries, and is particularly high in Asian countries. However, there is no multinational study using standardised measurements exploring variations in prescribing trends. OBJECTIVE: To compare polypharmacy trends in older people in Asia, Australia and the United Kingdom. DESIGN: Multinational, retrospective, time-trend, observational study using a common study protocol. SETTING: Outpatient and community settings. SUBJECTS: All individuals aged ≥ 65 years between 2013 and 2016. METHODS: We defined polypharmacy as the concomitant use of ≥5 medications for ≥45 days per year. We estimated the annual prevalence of polypharmacy and calculated average annual percentage change (AAPC) to assess the time trends. RESULTS: A total of 1.62 million individuals were included in this study. The highest prevalence of polypharmacy was observed in Hong Kong (46.4%), followed by Taiwan (38.8%), South Korea (32.0%), the United Kingdom (23.5%) and Australia (20.1%) in 2016. For the time trend, the Asian region showed a steady increase, particularly in Hong Kong and South Korea (AAPC: Hong Kong, 2.7%; South Korea, 1.8%; Taiwan, 1.0%). However, Australia and the United Kingdom showed a decreasing trend (Australia, -4.9%; the United Kingdom, -1.1%). CONCLUSIONS: Polypharmacy prevalence in older people was higher in Hong Kong, Taiwan and South Korea, with an increasing trend over time, compared with Australia and the United Kingdom. Our findings underline the necessity to monitor polypharmacy among older people in Asia by conducting government-level interventions and introducing medicine-optimisation strategies.

First-trimester exposure to benzodiazepines and risk of congenital malformations in offspring: A population-based cohort study in South Korea.

BACKGROUND: Benzodiazepines are frequently prescribed during pregnancy; however, evidence about possible teratogenicity is equivocal. We aimed to evaluate the association between first-trimester benzodiazepine use and the risk of major congenital malformations. METHODS AND FINDINGS: Using Korea's nationwide healthcare database, we conducted a population-based cohort study of women who gave birth during 2011 to 2018 and their live-born infants. The exposure was defined as one or more benzodiazepine prescriptions during the first trimester. We determined the relative risks (RRs) and confidence intervals (CIs) of overall congenital malformations and 12 types of organ-specific malformations. Infants were followed from birth to death or 31 December 2019, whichever came first (up to 8 years of age). Propensity score fine stratification was employed to control for 45 potential confounders. Among a total of 3,094,227 pregnancies, 40,846 (1.3%) were exposed to benzodiazepines during the first trimester (mean [SD] age, 32.4 [4.1] years). The absolute risk of overall malformations was 65.3 per 1,000 pregnancies exposed to benzodiazepines versus 51.4 per 1,000 unexposed pregnancies. The adjusted RR was 1.09 (95% CI 1.05 to 1.13, p < 0.001) for overall malformations and 1.15 (1.10 to 1.21, p < 0.001) for heart defects. Based on mean daily lorazepam-equivalent doses, the adjusted RRs for overall malformations and heart defects were 1.05 (0.99 to 1.12, p = 0.077) and 1.12 (1.04 to 1.21, p = 0.004) for <1 mg/day and 1.26 (1.17 to 1.36, p < 0.001) and 1.31 (1.19 to 1.45, p < 0.001) for >2.5 mg/day doses, respectively, suggesting a dose-response relationship. A small but significant increase in risk for overall and heart defects was detected with several specific agents (range of adjusted RRs: 1.08 to 2.43). The findings were robust across all sensitivity analyses, and negative control analyses revealed a null association. Study limitations include possible exposure misclassification, residual confounding, and restriction to live births. CONCLUSIONS: In this large nationwide cohort study, we found that first-trimester benzodiazepine exposure was associated with a small increased risk of overall malformations and heart defects, particularly at the higher daily dose. The absolute risks and population attributable fractions were modest. The benefits of benzodiazepines for their major indications must be considered despite the potential risks; if their use is necessary, the lowest effective dosage should be prescribed to minimize the risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT04856436.

Association between tramadol use and seizures: A nationwide case-case-time-control study.

PURPOSE: Tramadol may lower the seizure threshold; however, there is no conclusive evidence to confirm this. This study aimed to determine whether the use of tramadol is associated with the occurrence of seizures. METHODS: We conducted a case-case-time-control (CCTC) study by identifying patients who had received tramadol and seizure diagnosis in a nationwide healthcare database in South Korea between 2003 and 2015. Each case was matched for age and sex to one future case to adjust for time trends in exposure without selection bias from the use of an external control group. The use of tramadol was assessed during a risk period of 1-30 days, and two reference periods, 61-90 days and 91-120 days, preceding the first diagnosis of seizures. We calculated the adjusted odds ratio (aOR) by dividing the OR in cases (case-crossover) by the OR in future cases (control-crossover). We performed a dose-response analysis using the average daily dose. RESULTS: We identified 2523 incident cases with matched future cases (mean age, 45.4 years; 50% men). The aOR for seizure with tramadol use was 0.94 (95% confidence interval [CI], 0.98-1.43) in the CCTC analysis, with a case-crossover OR of 1.19 (0.98-1.43) and control-crossover OR of 1.27 (1.03-1.56). The dose-response analysis showed a similar trend in the main analysis: a low-dose aOR of 0.80 (0.50-1.28) and a high-dose aOR of 0.92 (0.41-2.11). CONCLUSION: We could not identify a significant association between transient use of tramadol and incidence of seizures in clinical practice.

Association Between Nonsteroidal Antiinflammatory Drug Use and Adverse Clinical Outcomes Among Adults Hospitalized With Coronavirus 2019 in South Korea: A Nationwide Study.

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) may exacerbate coronavirus disease 2019 (COVID-19) and worsen associated outcomes by upregulating the enzyme that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to in order to enter cells. METHODS: We conducted a cohort study using South Korea's nationwide healthcare database, which contains data for all individuals who received a COVID-19 test (n = 69 793) as of 8 April 2020. We identified adults hospitalized with COVID-19, where cohort entry was the date of hospitalization. NSAID users were those prescribed NSAIDs in the 7 days before and including cohort entry, and nonusers were those not prescribed NSAIDs during this period. Our primary outcome was a composite of in-hospital death, intensive care unit admission, mechanical ventilation use, and sepsis; our secondary outcomes were cardiovascular complications and acute renal failure. We conducted logistic regression analysis to estimate odds ratio (OR) with 95% confidence intervals (CIs) using inverse probability of treatment weighting to minimize confounding. RESULTS: Of 1824 adults hospitalized with COVID-19 (mean age, 49.0 years; female, 59%), 354 were NSAID users and 1470 were nonusers. Compared with nonuse, NSAID use was associated with increased risks of the primary composite outcome (OR, 1.54; 95% CI, 1.13-2.11) but insignificantly associated with cardiovascular complications (OR, 1.54; 95% CI, 0.96-2.48) or acute renal failure (OR, 1.45; 95% CI, 0.49-4.14). CONCLUSIONS: While awaiting the results of confirmatory studies, we suggest NSAIDs be used with caution for COVID-19 patients as the harms associated with their use may outweigh their benefits.

Real-world prescribing trends of valproate in women with epilepsy in Korea.

Avoiding valproate is recommended in women of childbearing age due to possible teratogenicity and infertility. We aimed to examine the recent trend of valproate prescriptions in Korea to review the adequacy of anticonvulsant prescriptions in women with epilepsy (WWE). Oral valproate utilization was assessed using nationwide and unselected data from the Korean National Health Insurance Service from 2009 to 2017. The temporal trends of the proportions of valproate prescriptions were analyzed using the Poisson regression model and expressed as average annual percentage change (AAPC). Among the WWE of childbearing age, valproate was prescribed in 37.0% overall and 29.4% as initial prescription in 2017. The proportion of valproate utilization showed a decreasing trend in overall prescription (AAPC = -1.10%) and initial prescription (AAPC = -2.63%). However, the proportion was static over time in the initial monotherapy group (AAPC = -0. 53%), while it was significantly decreasing in the initial polytherapy group (AAPC = -8.25%). A noticeable proportion of WWE was still being prescribed valproate in Korea. In particular, the use of valproate for initial monotherapy has not decreased over the past nine years. This result calls not only for reinforcement of education regarding anticonvulsant selection but also for monitoring the actual prescription.

Association between methylphenidate and risk of myocardial infarction: A multinational self-controlled case series study.

PURPOSE: To investigate the association between use of methylphenidate and risk of myocardial infarction among Asians. METHODS: We conducted a multinational self-controlled case series study using nationwide healthcare databases of South Korea (2002-2018), Taiwan (2004-2015), and Hong Kong (2001-2016). Of patients with myocardial infarction who were also prescribed methylphenidate within the observation period, methylphenidate use was classified into four mutually exclusive periods by each person-day: exposed (exposed to methylphenidate), pre-exposure (prior to the first methylphenidate prescription), washout (after the end of methylphenidate treatment), and baseline (unexposed to methylphenidate). Risk of myocardial infarction among the three periods of methylphenidate use was compared to the baseline period using conditional Poisson regression analysis to estimate incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: We identified 2104, 484, and 30 patients from South Korea, Taiwan, and Hong Kong, respectively. Risk of myocardial infarction was the highest during the pre-exposure period in all three populations: South Korea, pre-exposure (IRR 3.17, 95% CI 3.04-3.32), exposed (1.05, 1.00-1.11), washout (1.92, 1.80-2.04); Taiwan, pre-exposure (1.97, 1.78-2.17), exposed (0.72, 0.65-0.80), washout (0.56, 0.46-0.68); Hong Kong, pre-exposure (18.09, 8.19-39.96), exposed (9.32, 3.44-25.28), washout (7.69, 1.72-34.41). Following stratification for age and sex, the trends remained analogous to the main findings across all three populations. CONCLUSIONS: Although a positive association between initiating methylphenidate and the onset of myocardial infarction was observed, the risk was the highest in the period before its initiation. Thus, this multinational study suggests there was no causal relationship between methylphenidate and myocardial infarction among Asians.

Role of Luteolin-Induced Apoptosis and Autophagy in Human Glioblastoma Cell Lines.

Background and Objectives: Malignant glioblastoma (GBM) is caused by abnormal proliferation of glial cells, which are found in the brain. The therapeutic effects of surgical treatment, radiation therapy, and chemo-therapy against GBM are relatively poor compared with their effects against other tumors. Luteolin is abundant in peanut shells and is also found in herbs and other plants, such as thyme, green pepper, and celery. Luteolin is known to be effective against obesity and metabolic syndrome. The anti-inflammatory, and anti-cancer activities of luteolin have been investigated. Most studies have focused on the antioxidant and anti-inflammatory effects of luteolin, which is a natural flavonoid. However, the association between the induction of apoptosis by luteolin in GBM and autophagy has not yet been investigated. This study thus aimed to confirm the occurrence of luteolin-induced apoptosis and autophagy in GBM cells and to assess their relationship. Materials and Methods: A172 and U-373MG glioblastoma cell lines were used for this experiment. We confirmed the apoptosis effect of Luteolin on GBM cells using methods such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunofluorescence, Flow cytometry (FACS) western blot, and real-time quantitative PCR (qPCR). Results: In the luteolin-treated A172 and U-373MG cells, cell viability decreased in a concentration- and time-dependent manner. In addition, in A172 and U-373MG cells treated with luteolin at concentrations greater than 100 µM, nuclear fragmentation, which is a typical morphological change characterizing apoptosis, as well as fragmentation of caspase-3 and Poly (ADP-ribose) polymerase (PARP), which are apoptosis-related factors, were observed. Autophagy was induced after treatment with at least 50 µM luteolin. Inhibition of autophagy using 3MA allowed for a low concentration of luteolin to more effectively induce apoptosis in A172 and U-373MG cells. Conclusions: Results showed that luteolin induces apoptosis and autophagy and that the luteolin-induced autophagy promotes cell survival. Therefore, an appropriate combination therapy involving luteolin and an autophagy inhibitor is expected to improve the prognosis of GBM treatment.

Association between domperidone use and adverse cardiovascular events: A nested case-control and case-time-control study.

PURPOSE: To assess the association between domperidone and adverse cardiovascular events. METHODS: We conducted nested case-control and case-time-control studies using Korea's healthcare database (2002-2015). We identified patients without history of hospitalization, cancer, or cardiovascular diseases in 2002. From our cohort, those diagnosed with an adverse cardiovascular event (case), composite of arrhythmia, hypertension, or acute myocardial infarction were matched to two controls using risk-set sampling on various sociodemographic variables. Exposure was assessed in the 1 to 7 days, or in the 1 to 7 days (hazard period) and 91 to 97 days (control period) prior to index date, in nested case-control and case-time control studies, respectively. We compared domperidone to metoclopramide or non-use and estimated odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression. RESULTS: From 627 799 patients, we identified 71 555 cases and 141 833 controls. In the nested case-control study, while the risk of cardiovascular events was increased with domperidone (OR 1.38, 95% CI 1.28-1.47) compared to non-use, the risk was reduced (0.64, 0.57-0.72) compared to metoclopramide. In the case-time-control study, similar increased risk was found when compared to non-use (1.40, 1.29-1.52) but a reduced risk as compared with metoclopramide (0.63, 0.54-0.72). Risk of myocardial infarction associated with domperidone was highest (nested case-control: 1.94, 1.33-2.83; case-time-control: 1.91, 1.01-3.62) when compared to non-use but did not indicate an increased risk when compared to metoclopramide (nested case-control: 0.60, 0.32-1.13; case-time-control: 0.70, 0.25-1.98). CONCLUSION: Our findings support a positive association between domperidone and adverse cardiovascular events. However, domperidone may have a safer cardiovascular profile than metoclopramide.

Beyond uncertainty: Negative findings for the association between the use of proton pump inhibitors and risk of dementia.

OBJECTIVES: We investigated the risk of dementia associated with the use of proton pump inhibitors (PPIs) as compared with the use of histamine-2 receptor antagonist (H2RA). METHODS: We conducted retrospective propensity score-matched cohort study using the National Health Insurance Service-National Sample Cohort. Subjects were defined as the patients newly prescribed with PPI or H2RA between 2003 and 2013 without prior prescriptions of PPI/H2RA or diagnosis of dementia from their history within the past 1 year. We followed up participants until dementia occurrence, death, or the end of the study, whichever occurred first, with an intention-to-treat approach. A 1-year lag time between exposure and outcome measure was used to reduce protopathic bias. The incidence rate per 1000 person-years was estimated. The incidence rate of PPI was compared with that of H2RA, defined as incidence rate ratio (IRR), calculated with a 95% confidence interval. To control for potential confounds, propensity score matching at a 1:1 ratio was conducted, and the crude IRR was adjusted by risk factors. RESULTS: Our propensity score-matched cohort included 87 562 patients on PPIs and 87 562 patients on H2RAs. The IRR was 1.01 (95% confidence interval 0.96-1.06) with 1-year lag time. IRR showed the decreased trend as the longer lag time. Also, no treatment duration or dose-response relationship was observed. CONCLUSIONS: Our finding demonstrated that PPIs did not associate with dementia more strongly than did H2RA. On this basis, we suggest that the previously reported risk for dementia associated with PPI may have been overestimated.

Regulatory effect of decreasing therapeutic duplication of respiratory drugs using a prescription database between 2012 and 2015.

Duplicative drug use increases the risk of adverse drug reactions and expends healthcare resources unnecessarily. No epidemiological evidence of the prevalence of therapeutic duplication (TD) involving respiratory system drugs exists. Therefore, we describe the prescription patterns of these drugs and estimate changes in TD rates following implementation of a new regulation in 2013. A time-series analysis using national healthcare data was conducted, involving eight classes, and patients prescribed any of these drugs between 2012 and 2015. We used two definitions of TD; duplicative prescriptions overlapped for more than 30 days by the same prescriber and for more than 1 day by different prescribers. We calculated relative and absolute difference in TD rates after the regulation. TD by the same prescriber decreased for respiratory drugs of six classes, but increased more than 10% for antihistamines (+10.28, +0.05). TD by a different prescriber decreased only for xanthine bronchodilators, but increased more than 10% for beta-receptor agonists (+27.07, +1.42), leukotriene receptor antagonists (+16.10, +0.44), cough suppressants (+15.64, +0.52), mucolytic agents (+11.16, +0.67). The 2013 regulation regarding respiratory drugs did not have the anticipated effect of reducing TD prevalence; more effective interventions are needed.

Portal Connecting Dark Photons and Axions.

The dark photon and the axion (or axionlike particle) are popular light particles of the hidden sector. Each of them has been actively searched for through the couplings called the vector portal and the axion portal. We introduce a new portal connecting the dark photon and the axion (axion-photon-dark photon, axion-dark photon-dark photon), which emerges in the presence of the two particles. This dark axion portal is genuinely new couplings, not just from a product of the vector portal and the axion portal, because of the internal structure of these couplings. We present a simple model that realizes the dark axion portal and discuss why it warrants a rich phenomenology.

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.

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.