Pfizer (South Korea)

Breast cancer (BC) in the Asia Pacific regions is enriched in younger patients and rapidly rising in incidence yet its molecular bases remain poorly characterized. Here we analyze the whole exomes and transcriptomes of 187 primary tumors from a Korean BC cohort (SMC) enriched in pre-menopausal patients and perform systematic comparison with a primarily Caucasian and post-menopausal BC cohort (TCGA). SMC harbors higher proportions of HER2+ and Luminal B subtypes, lower proportion of Luminal A with decreased ESR1 expression compared to TCGA. We also observe increased mutation prevalence affecting BRCA1, BRCA2, and TP53 in SMC with an enrichment of a mutation signature linked to homologous recombination repair deficiency in TNBC. Finally, virtual microdissection and multivariate analyses reveal that Korean BC status is independently associated with increased TIL and decreased TGF-β signaling expression signatures, suggesting that younger Asian BCs harbor more immune-active microenvironment than western BCs.

To elucidate the effects of neoadjuvant chemotherapy (NAC), we conduct whole transcriptome profiling coupled with histopathology analyses of a longitudinal breast cancer cohort of 146 patients including 110 pairs of serial tumor biopsies collected before treatment, after the first cycle of treatment and at the time of surgery. Here, we show that cytotoxic chemotherapies induce dynamic changes in the tumor immune microenvironment that vary by subtype and pathologic response. Just one cycle of treatment induces an immune stimulatory microenvironment harboring more tumor infiltrating lymphocytes (TILs) and up-regulation of inflammatory signatures predictive of response to anti-PD1 therapies while residual tumors are immune suppressed at end-of-treatment compared to the baseline. Increases in TILs and CD8+ T cell proportions in response to NAC are independently associated with pathologic complete response. Further, on-treatment immune response is more predictive of treatment outcome than immune features in paired baseline samples although these are strongly correlated.

OBJECTIVE: Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment. METHODS: We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [(11) C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes. RESULTS: Parietal and occipital lobar CMBs counts were higher in PiB(+) ADCI with moderate WMH than PiB(+) ADCI with minimal WMH, whereas PiB(-) patients with SVCI (ie, "pure" SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001). INTERPRETATION: Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs.

Tick-borne encephalitis virus (TBEV) causes mild or moderate febrile illness in humans that may progress to encephalitis, leading to severe long-term complications and sometimes death. TBEV is prevalent in the Eurasian continent and has been isolated in China, Japan and Republic of Korea (ROK). The TBEV isolates from Japan are of the Far-Eastern subtype; in ROK, the isolates are of the Western subtype; and all TBEV isolates in China are of the Far-Eastern subtype, except one strain that was identified most recently as the Siberian subtype. TBE is endemic to the northeast, northwest and southeast of China; only two confirmed TBE cases have been reported in Japan to date; and no TBE case has been confirmed in ROK. For TBE patients in China, the onset of disease is acute with no biphasic course for disease presentation. The clinical spectrum of disease phenotypes may be wider than currently understood, since serological evidence suggests the presence of TBEV infections in healthy people, indicating that asymptomatic or unspecific manifestations of TBEV infection may exist. The current treatment for TBE is supportive care. In China, vaccines against TBEV have been developed and are available with demonstrated immunogenicity and safety, although efficacy data are lacking. No vaccines are available in ROK or Japan.

BACKGROUND/AIMS: This study aimed to investigate treatment patterns and medication adherence of glaucoma. It also identified key factors associated with non-adherence. METHODS: It was a cross-sectional, observational study. Patients who use eye-drops for ≤2 years were recruited at 15 eye clinics from March to November 2013. Data were collected through self-administered questionnaires and medical chart review. Medication adherence was evaluated using patients' self-report on pill count and defined as patients' administering drug for ≥80% of prescribed days. Medication adherence rate was calculated by dividing actual number of administration from total prescribed number of administration for 7 days. Patients whose self-reported prescription was different from total daily doses of physicians' prescription were considered as non-adherent. RESULTS: A total of 1050 patients included, and medication adherence rate was evaluated in 1046 patients whose verification of adherence was available. Of the total, 27.4% were non-adherent, and the medication adherence rates of the total, the adherent, and the non-adherent were 90.6±17.8%, 96.8±5.5% and 56.6±24.7%, respectively. The most commonly used medication was prostaglandin (PGA) alone and the second was combination of two-class (β-blocker and carbonic anhydrase inhibitor (CAI)) and three-class combination of PGA, β-blocker and CAI followed. In multivariate analysis, the risk of non-adherence was 1.466 times greater in males than in females (95% CI 1.106 to 1.943) and 1.328-fold greater as the daily number of administration was increased (95% CI 1.186 to 1.487). CONCLUSION: Approximately, one-third of the patients were non-adherent, and males and increased daily number of administration were associated with non-adherence. It highlights that more systematic treatment strategies should be considered for better medication adherence, leading to effective glaucoma management.

BACKGROUND: Heterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features. METHODS: We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets. RESULTS: Based on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations. CONCLUSION: Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.

This paper describes a simulation model of capital budgeting under uncertainty. It analyzes the effects of two types of uncertainty which influence the cash flows of the potential investment projects. Techniques of simulation and stochastic linear programming (using Weingartner's Basic Horizon model of capital budgeting) are employed to compute the expected return (with an associated measure of the risk involved) of different portfolios of projects. The manager can then select the portfolio which is closest to his personal risk-return preference. The model provides a practical guide to management in the entire process of project search, portfolio generation, and portfolio evaluation which characterizes the capital budgeting decision.

PURPOSE: Asthma-related morbidity and mortality are increasing, and the financial burden imposed by this condition will substantially increase. Nevertheless, little information is available regarding the nature and magnitude of the burden due to asthma at the national level. This study was conducted to characterize the financial burden imposed by asthma in the Republic of Korea at the national level. METHODS: The overall prevalence of asthma and the costs of related medical services were determined using data from the National Health Insurance Corporation, which is responsible for the National Health Insurance scheme. Indirect costs, including expenditures on complementary and alternative medicines, and the economic impact of an impaired quality of life (intangible costs) were estimated by surveying 660 asthmatics, and these estimates were transformed to the national level using the prevalence of asthma. RESULTS: The prevalence of asthma and total costs related to the disease in 2004 were 4.19% and $2.04 billion, respectively. Direct costs and indirect costs contributed equally to total costs (46.9% and 53.1%, respectively). However, when intangible costs were included, total costs rose to $4.11 billion, which was equivalent to 0.44% of the national gross domestic product in 2004. CONCLUSIONS: The results provide evidence that asthma is a major health cost factor in the Republic of Korea and that intangible costs associated with asthma are significant cost drivers.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. METHODS: Tissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. RESULTS: Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. CONCLUSIONS: We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.

BACKGROUND: Major depressive disorder (MDD) is strongly associated with an impaired quality of life (QoL), which is itself affected by various factors. Symptom-oriented ratings poorly reflect the impact of disease on the QoL and level of functioning of the mental health of subjects. The purpose of this study was to assess health-related QoL (HRQoL) using preference-based measures in outpatients with MDD with regard to their remission achievement and clinical factors affecting the HRQoL. METHODS: This was a cross-sectional observational study. We recruited 811 patients with MDD from 14 psychiatric outpatient clinics in Korea. They were divided into three groups as follows: a new visit group (n = 287), a remitted group (n = 235), and a non-remitted group (n = 289). The 17-item Hamilton Depression Rating Scale was used to assign patients to the remitted or non-remitted group. The general HRQoL was assessed with the EuroQol 5D (EQ-5D), using both the EQ-5D index score and the EuroQol Visual Analog Scale (EQ-VAS). The disease-specific HRQoL was assessed with the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). RESULTS: The non-remitted group showed a significant impairment of HRQoL in view of the subscales of EQ-5D index scores, EQ-VAS, and Q-LES-Q-SF. The EQ-5D index score in the remitted group was 0.77 ± 0.10, while it was 0.57 ± 0.23 in the non-remitted group and 0.58 ± 0.24 in the new visit group (p < 0.0001). The EQ-VAS scores for the remitted and non-remitted groups were 72.5 ± 16.6 and 50.9 ± 20.3, respectively (p < 0.0001). Likewise, patients with remission had the Q-LES-Q-SF total score of 46.5 ± 8.8, whereas those with non-remission reported 36.7 ± 7.7 (p < 0.0001). The symptom severity measured by the Depression and Somatic Symptoms Scale was significantly correlated with the HRQoL. Furthermore, patients with severe somatic symptoms showed a significantly lower EQ-5D index score (0.54 ± 0.24) than those with mild/moderate somatic symptoms (0.75 ± 0.12; p = 0.002). CONCLUSION: Non-remitted MDD patients, especially those with more severe somatic symptoms, show a distinct impairment of HRQoL and more clinical symptoms, suggesting the importance of achieving remission in the treatment of MDD.

BACKGROUND: Recent advances in resting-state functional MRI have revealed altered functional networks in Alzheimer's disease (AD), especially those of the default mode network (DMN) and central executive network (CEN). However, few studies have evaluated whether small vessel disease (SVD) or combined amyloid and SVD burdens affect the DMN or CEN. OBJECTIVE: The aim of this study was to evaluate whether SVD or combined amyloid and SVD burdens affect the DMN or CEN. METHODS: In this cross-sectional study, we investigated the resting-state functional connectivity within DMN and CEN in 37 Pittsburgh compound-B (PiB)(+) AD, 37 PiB(-) subcortical vascular dementia (SVaD), 13 mixed dementia patients, and 65 normal controls. RESULTS: When the resting-state DMN of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(+) AD patients displayed lower functional connectivity in the inferior parietal lobule while the PiB(-) SVaD patients displayed lower functional connectivity in the medial frontal and superior frontal gyri. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the DMN in the posterior cingulate gyrus. When the resting-state CEN connectivity of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(-) SVaD patients displayed lower functional connectivity in the anterior insular region. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the CEN in the inferior frontal gyrus. CONCLUSIONS: Our findings suggest that in PiB(+) AD and PiB(-) SVaD, there is divergent disruptions in resting-state DMN and CEN. Furthermore, patients with combined amyloid and SVD burdens exhibited more disrupted resting-state DMN and CEN than patients with only amyloid or SVD burden.

PURPOSE: We evaluated the safety and effectiveness of the Magnetic Resonance-guided Focused Ultrasound (MRgFUS) with the ExAblate Conformal Bone System for the palliation of painful bone metastases. MATERIALS AND METHODS: Our Institutional Review Board approved this study, and all patients gave informed consent prior to enrollment. A total of six painful metastatic bone lesions in five patients were treated using MRgFUS with the ExAblate Conformal Bone System for pain palliation. The follow-up sessions were at 3 days, 2 weeks, 1, 2, and 3 months, and 1 year after treatment. Efficacy was evaluated by the changes in visual analog scale (VAS) scores. At 3-months and 1-year follow-ups, unenhanced computed tomography and contrast-enhanced MR imaging examinations were performed. All adverse events were assessed to evaluate treatment safety. RESULTS: All patients showed significant pain relief within 2 weeks. Two patients experienced complete pain reduction that lasted for 1 year. Two other patients showed pain relief measured as VAS scores of 2 and 4 on their last follow-up. Although the remaining patient had experienced significant pain relief in two lesions, the VAS score re-increased on his last follow-up. The size of the enhancing soft tissue mass in metastatic lesions decreased, and new bone formation was seen on follow-up images. Although adverse events were not serious, non-specific leg pain and second degree skin burn were noted. CONCLUSION: MRgFUS was demonstrated to be effective palliative treatment within 2 weeks in selected patients with painful bone metastases.

Incidence, epidemiology, and risk factors of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients can vary from different cohorts and countries. Therefore, we performed a nationwide study to establish a proper antifungal prophylaxis strategies based on risk stratifications of IFDs after all-HSCT in Korea (RISK study). This was a multicenter, retrospective, and observational study in Korea. All consecutive adult patients who received allo-HSCT in 2013 were included. The 12-month cumulative incidence of proven/probable IFDs (PP-IFDs) was calculated during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT. Cox proportional hazard regression analysis was performed to identify risk factors for PP-IFDs at each phase. A total 521 allo-HSCT cases in 518 patients were analyzed. Overall cumulative incidence of PP-IFDs were 4.09% (95% confidence interval [CI], 2.38 to 5.81), 7.38% (95% CI, 5.09 to 9.67), and 15.36% (95% CI, 12.04 to 18.68) at the early, late and very phases, respectively. In multiple Cox regression analysis, variables were associated with PP-IFDs in each period were identified. Variables associated with early phase include underlying pulmonary diseases, underlying nonmalignant stable or chronic disease at allo-HSCT, unrelated or family mismatched donor, and prolonged neutropenia. Variables associated with the late phase include high ferritin level at the time point of allo-HSCT, use of secondary immunosuppressive agents due to refractory graft-versus-host disease (GVHD), and cytomegalovirus reactivation. For the very late phase, variables were secondary neutropenia, severe chronic GVHD, and use of TNF-alpha inhibitor for refractory GVHD. This study revealed the high cumulative incidence of IFDs in Korean allo-HSCT recipients, which have distinct risk factors in each phase after allo-HSCT. Our findings indicate that tailored antifungal prophylaxis is necessary for high-risk patients. Clinicians should consider using mold-active antifungal prophylaxis in allo-HSCT recipients who have high risks at different treatment period.

PURPOSE: Neuropathic cancer pain (NCP) is a common and potentially debilitating symptom in cancer patients. We investigated the prevalence of NCP, as well as its management and association with QOL. METHODS: Cancer patients with pain ≥1 on the visual analogue scale (VAS) were surveyed with the Douleur Neuropathique (DN4) questionnaire, the Brief Pain Inventory-Short Form (BPI-SF), and the EuroQOL five dimensions (EQ-5D) questionnaire. The associations between NCP and pain severity or NCP and QOL, while controlling for variables relevant to QOL, were then analyzed. RESULTS: A total of 2003 patients were enrolled in this survey; the prevalence of NCP was 36.0% (n = 722, 95% CI, 32.5-39.5). We found that NCP in cancer patients was closely correlated to a higher pain severity (BPI-SF; 4.96 ± 1.94 versus 4.24 ± 2.02, p < 0.001), and in patients with NCP, pain more severely interfered with daily living, as compared to those without NCP (BPI-SF; 4.86 ± 2.71 versus 4.41 ± 2.87, p < 0.001). Patients with NCP also had worse QOL than those without NCP, as measured by EQ-5D index score (0.47 ± 0.30 vs. 0.51 ± 0.30, p = 0.005), and this was confirmed using multivariate analysis (p < 0.001), even after controlling for other variables such as age, sex, disease stage, cancer duration, radiotherapy, chemotherapy, and comorbidities. Importantly, adjuvant analgesics were used in less than half of patients with NCP (n = 358, 46.4%). CONCLUSIONS: We found that NCP in cancer patients was significantly associated with a worsened QOL, and current management is inadequate. Therefore, future research aimed at developing improved strategies for management of NCP is required.

Although statins are established therapy for the secondary prevention of ischemic stroke, factors associated with adherence to statin treatment following ischemic stroke are not well known. To address this, we assessed the 6-month statin adherence using 8-item Morisky Medication Adherence Scale-8 in patients with acute ischemic stroke. Of 991 patients, 65.6% were adherent to statin at 6-month after discharge. Multiple logistic regression analysis showed that patients' awareness of hyperlipidemia (OR 1.62; 95% CI 1.07-2.43), large artery stroke subtype (versus non-large artery stroke, OR 1.79; 95% CI 1.19-2.68), and alcohol drinking habits (OR 1.64; 95% CI 1.06-2.53) were positively associated, while high statin dose (versus low dose, OR 0.6; 95% CI 0.40-0.90) and higher daily number of medication pills (OR 0.93; 95% CI 0.88-0.97) were found to have a negative association with self-reported good adherence to statin medication after acute ischemic stroke. However, stroke severity and diagnosis of hyperlipidemia were not associated with adherence. These results suggest that educational and motivational interventions may enhance statin adherence because modifiable factors were associated with statin adherence.

BACKGROUND: Etanercept, a soluble tumor necrosis factor receptor, and acitretin have been shown to be effective in treating psoriasis. Acitretin is widely used in Korea. However, the combination of etanercept plus acitretin has not been evaluated among Korean patients with psoriasis. The objective of this study was to investigate the efficacy and safety of combination therapy with etanercept and acitretin in patients with moderate to severe plaque psoriasis. METHODS: Sixty patients with psoriasis were randomized to receive etanercept 50 mg twice weekly (BIW) for 12 weeks followed by etanercept 25 mg BIW for 12 weeks (ETN-ETN); etanercept 25 mg BIW plus acitretin 10 mg twice daily (BID) for 24 weeks (ETN-ACT); or acitretin 10 mg BID for 24 weeks (ACT). The primary efficacy measurement was the proportion of patients achieving 75 % improvement in Psoriasis Area and Severity Index (PASI 75) at week 24. Secondary end points included 50 % improvement in PASI (PASI 50) at week 24 and clear/almost-clear by Physician Global Assessment (PGA) at each visit through week 24. RESULTS: The proportions of patients achieving PASI 75, PASI 50, and PGA clear/almost-clear at week 24 in the ETN-ETN (52.4, 71.4, and 52.4 %, respectively) and ETN-ACT groups (57.9, 84.2, and 52.6 %, respectively) were higher than in the ACT group (22.2, 44.4, and 16.7 %, respectively). The incidence of adverse events was similar across all arms. This was an open-label study with a small number of patients. CONCLUSION: In Korean patients with moderate to severe plaque psoriasis, etanercept alone or in combination with acitretin was more effective than acitretin. All treatments were well tolerated throughout the study. TRIAL REGISTRATION: This study was registered on July 7, 2009 at ClinicalTrials.gov, NCT00936065 .

The assessment of health-related quality of life (HRQoL) as a patient-reported outcome provides information about the patients' general well-being as well as the effects of the disease and its treatment. This study aimed to investigate HRQoL using both generic and haemophilia-specific QoL instruments and to assess the clinical factors associated with HRQoL among haemophilia patients in Korea. In this cross-sectional, multicenter, observational study, moderate-to-severe haemophilia patients aged 8-64 years were recruited between November 2012 and September 2013. The EQ-5D Questionnaire, EQ Visual Analogue Scale, and Haemophilia-Specific QoL (Haemo-QoL) Questionnaire (Haemo-QoL for 8-16 years and Haemo-A-QoL for ≥17 years) were used to assess HRQoL. A total of 605 participants with a mean age of 29.32 ± 12.62 years were enrolled. The mean Haemo-QoL scores revealed significant differences by age group (children vs. adolescent vs. adult, 26.44 ± 11.3 vs. 28.88 ± 11.1 vs. 38.43 ± 17.7, respectively, p < 0.001). "Sports and leisure," "family planning," and "view" in adults and "perceived support," "friends," and "dealing" in children and adolescents were identified as the domains with the greatest HRQoL impairments. HRQoL was significantly impaired in patients with the following clinical factors: hepatitis, haemophilia-induced disability, bleeding experiences within the last 6 months, joint bleedings within the last 6 months, and haemophilic arthropathy. According to the multivariate regression analysis, HRQoL showed a negative association with the presence of haemophilia-induced disability (β = 0.222, p < 0.0001), bleeding experiences within the last 6 months (β = 0.098, p = 0.010), and haemophilic arthropathy (β = 0.212, p < 0.0001). HRQoL decreased in patients with older age and impaired clinical conditions among moderate-to-severe haemophilia patients in Korea. These study findings may provide significant insights into the adequate haemophilia management using patient-reported measurements.

Background Although randomized trials provide a high level of evidence regarding the efficacy of non-vitamin K oral anticoagulants (NOACs), the results of such trials may differ from those observed in day-to-day clinical practice. Aims To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between NOAC and warfarin in clinical practice. Methods Patients with non-valvular atrial fibrillation (NVAF) who started warfarin/NOACs between January 2015 and November 2016 were retrospectively identified from Korea’s nationwide health insurance claims database. Using inpatient diagnosis and imaging records, the Cox models with inverse probability of treatment weighting using propensity scores were used to estimate hazard ratios (HRs) for NOACs relative to warfarin. Results Of the 48,389 patients, 10,548, 11,414, 17,779 and 8,648 were administered apixaban, dabigatran, rivaroxaban and warfarin, respectively. Many patients had suffered prior strokes (36.7%, 37.7%, 31.4%, and 32.2% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), exhibited high CHA 2 DS 2 -VASc (4.8, 4.6, 4.6, and 4.1 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) and HAS-BLED (3.7, 3.6, 3.6, and 3.3 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) scores, had received antiplatelet therapy (75.4%, 75.7%, 76.8%, and 70.1% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), or were administered reduced doses of NOACs (49.8%, 52.9%, and 42.8% in apixaban, dabigatran, and rivaroxaban group, respectively). Apixaban, dabigatran and rivaroxaban showed a significantly lower S/SE risk [HR, 95% confidence intervals (CI): 0.62, 0.54–0.71; 0.60, 0.53–0.69; and 0.71, 0.56–0.88, respectively] than warfarin. Apixaban and dabigatran (HR, 95% CI: 0.58, 0.51–0.66 and 0.75, 0.60–0.95, respectively), but not rivaroxaban (HR, 95% CI: 0.84, 0.69–1.04), showed a significantly lower MB risk than warfarin. Conclusions Among Asian patients who were associated with higher bleeding risk, low adherence, and receiving reduced NOAC dose than that provided in randomised controlled trials, all NOACs were associated with a significantly lower S/SE risk and apixaban and dabigatran with a significantly lower MB risk than warfarin.

Importance: The use of oral corticosteroids for prolonged periods may be associated with adverse events (AEs). Nevertheless, the risk of AEs with oral corticosteroids, especially among patients with atopic dermatitis (AD), has not been comprehensively investigated and lacks evidence on duration of treatment. Objective: To assess the association between long-term exposure to oral corticosteroids and AEs among adult patients with AD. Design, Setting, and Participants: This nested case-control study used data from the Health Insurance Review and Assessment Service database of South Korea between January 1, 2012, and October 31, 2021, which included 1 year prior to the cohort entry date of January 1, 2013, for assessing exclusion criteria and baseline characteristics, and 1 year after the study end date of October 31, 2020, to ensure a minimum duration for assessing exposure. Among the population of adults with AD, patients diagnosed with any of 11 AEs were matched with patients who had never received a diagnosis of any of the 11 AEs. Exposure: Long-term use of oral corticosteroids was defined as cumulative supply of more than 30 days or more than 90 days of oral corticosteroid prescription per year. Main Outcomes and Measures: We used multivariable conditional logistic regression analyses to measure the risk of 11 individual outcomes (osteoporosis, fracture, type 2 diabetes, hyperlipidemia, hypertension, myocardial infarction, stroke, heart failure, avascular necrosis, cataract, or glaucoma) as the composite outcome, controlling for potential confounders. We further classified the composite outcome to individual outcomes to evaluate the AE-specific risk. Results: Among 1 025 270 patients with AD between 2013 and 2020, 164 809 cases (mean [SD] age, 39.4 [14.8]; 56.9% women) were matched with 328 303 controls (mean [SD] age, 39.3 [14.7]; 56.9% women) for sex, age, cohort entry date, follow-up duration, and severity of AD, where the balance of most baseline characteristics was achieved. A total of 5533 cases (3.4%) and 10 561 controls (3.2%) were exposed to oral corticosteroids for more than 30 days, while 684 cases (0.4%) and 1153 controls (0.4%) were exposed to oral corticosteroids for more than 90 days. Overall, there was no increased risk of AEs with use of oral corticosteroids for more than 30 days (adjusted odds ratio [AOR], 1.00; 95% CI, 0.97-1.04), whereas the risk was slightly higher with use of oral corticosteroids for more than 90 days (AOR, 1.11; 95% CI, 1.01-1.23). The small elevation in experiencing an AE was observed with each cumulative or consecutive year of ever long-term use. Conclusions and Relevance: This case-control study found a slightly increased risk of AEs associated with use of oral corticosteroids for more than 90 days per year, which warrants future research to fully elucidate the observed findings.

BACKGROUND: Failure mode and effects analysis (FMEA) is a risk management tool to proactively identify and assess the causes and effects of potential failures in a system, thereby preventing them from happening. The objective of this study was to evaluate effectiveness of FMEA applied to an academic clinical trial center in a tertiary care setting. METHODS: A multidisciplinary FMEA focus group at the Seoul National University Hospital Clinical Trials Center selected 6 core clinical trial processes, for which potential failure modes were identified and their risk priority number (RPN) was assessed. Remedial action plans for high-risk failure modes (RPN >160) were devised and a follow-up RPN scoring was conducted a year later. RESULTS: A total of 114 failure modes were identified with an RPN score ranging 3-378, which was mainly driven by the severity score. Fourteen failure modes were of high risk, 11 of which were addressed by remedial actions. Rescoring showed a dramatic improvement attributed to reduction in the occurrence and detection scores by >3 and >2 points, respectively. CONCLUSIONS: FMEA is a powerful tool to improve quality in clinical trials. The Seoul National University Hospital Clinical Trials Center is expanding its FMEA capability to other core clinical trial processes.