Association between selective serotonin reuptake inhibitor use and developing irritable bowel syndrome through retrospective analysis.

BACKGROUND AND AIM: Serotonin affects the balance and integrity of the gut microbiome; however, studies have confirmed the influence of selective serotonin reuptake inhibitors (SSRIs) on irritable bowel syndrome (IBS). We evaluated the association between SSRI use and subsequent IBS occurrence in a real-world setting. METHODS: A multivariate Cox proportional hazard model was adopted, and the National Health Insurance Service cohort claims database between 2010 and 2019 was used. Non-SSRI users were selected using the propensity score matching method. Subgroup analyses were performed using the point of use, cumulative dose, and duration of SSRI use. Additional analysis was performed using a control group without psychiatric medications. RESULTS: We included 2901 SSRI users and 2727 non-SSRI users. After adjusting covariates, the risk of developing IBS in SSRI users was 1.54 times that in non-SSRI users (95% confidence interval [CI]: 1.01-2.33). The hazard ratio (HR) of the recent, heavy, and short-term user groups were 3.19 (95% CI: 2.03-4.99), 2.22 (95% CI: 1.50-3.29), and 4.83 (95% CI: 3.02-7.73), respectively, compared with that of non-users. In patients without a history of psychiatric medications, the risk of IBS incidence after SSRI use increased significantly (HR: 1.61, 95% CI: 1.06-2.42), whereas HR was insignificant in patients with a history of psychiatric medications (HR: 1.25, 95% CI: 0.98-1.60). CONCLUSIONS: The risk of subsequent IBS occurrence following SSRI use was high in patients who initially took a heavy SSRI dose and those who did not have a history of psychiatric drug use.

Health disparity and healthcare utilization inequity among older adults living in poverty in South Korea: a cross-sectional study.

BACKGROUND: Korea has a two-tiered universal health security system: the wage-based National Health Insurance (NHI) program and government-subsidized Medical Aid (MA) program. Beneficiaries of the MA program belong to the lowest economic class. This study aims to investigate the association between economic status-defined as NHI or MA enrollment-and health disparity of older people aged ≥ 65 years in South Korea. METHODS: The claims records of 672,525 older age population from the 2017 Health Insurance Review and Assessment Service-Adult Patient Sample were used to estimate adjusted odds ratios (aORs) of MA vs. NHI beneficiaries for prevalence for common geriatric diseases. Logistic regression and negative binomial regression were used to investigate the association between economic status and prevalence or healthcare utilization for each disease. RESULTS: MA beneficiaries showed significantly higher prevalence than NHI beneficiaries for seven out of nine diseases (aORs ranging from 1.18 to 1.95). The discrepancy in the prevalence between the two groups was highest among those aged 65-69 years (aORs: 1.34-2.94), and diminished as they got older (aORs: 1.05-1.67). MA beneficiaries had significantly more outpatient visits to treat six diseases (aORs: 1.07-1.28), and more hospitalization to treat seven diseases (aORs:1.08-1.73) than NHI beneficiaries. CONCLUSION: The higher prevalence of common geriatric diseases among MA than NHI beneficiaries confirms unfavorable health disparity in the elderly living in extreme poverty. Similar or higher healthcare utilization in treating the same conditions among MA beneficiaries suggests a low possibility of inequity for access to healthcare resources covered by the universal health security system due to poor economic status. Greater excess use of inpatient than outpatient care by MA beneficiaries implies that the condition of poor older adults might be more severe when diagnosed with the same disease.

Prevalence and patterns of the concurrent use of anticholinergics for the motor symptoms of Parkinson's disease and acetylcholinesterase inhibitors in Parkinson's disease patients with dementia: a cross-sectional study using Korea National Health Insurance claims data.

BACKGROUND: The concurrent use of anticholinergics and acetylcholinesterase inhibitors (ACHEIs) in Parkinson's disease (PD) patients with dementia should be avoided because the opposing pharmacological actions of both drugs reduce the treatment efficacy. We aimed to investigate the prevalence of the concurrent use of these two types of drugs in Korean patients. METHODS: In the 2017 Health Insurance Review and Assessment Service-National Aged Patient Sample data, comprising insurance claims records for a 10% random sample of patients aged ≥ 65 years in Korea, "concurrent use" was defined as the overlapping of anticholinergic and ACHEI doses for at least 2 months. RESULTS: Among 8,845 PD patients with dementia, 847 (9.58%) were co-administered anticholinergics, used to treat the motor symptoms of PD, and ACHEIs for a mean duration of 7.7 months. A total of 286 (33.77% of all co-administered) patients used both drug types concurrently all year. About 80% of concurrent users were prescribed each drug by the same prescriber, indicating that coadministration may not be due to a lack of information sharing between providers. Logistic regression analysis showed that patients mainly treated at clinics (odds ratio (OR), 1.541; 95% confidence interval (CI), 1.158-2.059), hospitals (OR, 2.135; 95% CI, 1.586-2.883), and general hospitals (OR, 1.568; 95% CI, 1.221-2.028) were more likely to be co-prescribed anticholinergics and ACHEIs than those mainly treated at tertiary-care hospitals. PD patients with dementia treated at healthcare organizations located in areas other than the capital city had an approximately 22% higher risk of concurrent use (OR: 1.227, 95% CI: 1.046-1.441). CONCLUSIONS: The concurrent use of anticholinergics for the motor symptoms of PD and ACHEIs in elderly Korean PD patients with dementia cannot be ignored, and strategies that mitigate potentially inappropriate concurrent drug use are required.

Cost-utility analysis of emicizumab prophylaxis in haemophilia A patients with factor VIII inhibitors in Korea.

AIMS: Haemophilia A patients with factor VIII inhibitors (HAPI) experience frequent spontaneous bleeding, approximately once a week, and require expensive bypassing agent (BPA) treatments to control bleeding over their lifetime. According to the HAVEN 1 trial, weekly emicizumab (Hemlibra®) prophylaxis injection reduces annualized bleeding rates (ABR) by 87% compared with BPA on-demand treatment (BPA-OD) administered at the time of bleeding. Our study aimed to assess the cost-effectiveness of emicizumab prophylaxis in HAPI in Korea. METHODS: Using a lifetime Markov model with health states of 'alive with bleeds' and 'dead', we simulated the experience of HAPI receiving emicizumab prophylaxis (treatment arm) or BPA-OD (control arm) and estimated expected clinical and economic outcomes under each treatment arm. Model parameters included comparative effectiveness, clinical and epidemiologic characteristics of Korean HAPI, costs of drug treatment and medical events and utility for 'alive with bleeds' state under each treatment. We utilized local data, including National Health Insurance claims data, national statistics, literature and expert surveys with haematologists. RESULTS: Base-case analysis results showed that compared with BPA-OD, lifetime emicizumab prophylaxis prevented 807 bleedings, extended 3.04 quality-adjusted life-years and reduced costs by 2.6 million US dollars. Thus, emicizumab prophylaxis is a dominant treatment option with better effectiveness and lower costs than BPA-OD. A series of one-way sensitivity analyses consistently showed dominant results, confirming that lifetime emicizumab prophylaxis is a cost-saving intervention for HAPI. CONCLUSION: Emicizumab prophylaxis is an excellent treatment choice reducing ABR, improving quality of life and reducing costs.

Association between depression and antibiotic use: analysis of population-based National Health Insurance claims data.

BACKGROUND: Frequent exposure to antibiotic treatments may increase the risk of antibiotic resistance, which may threaten the effectiveness of future antibiotic treatments. Thus, it is important to identify the preventable risks in terms of antibiotic use. This study assessed the association between major depressive disorder (MDD) and antibiotic use by comparing the likelihood and extent of antibiotic use between patients with and without MDD. METHODS: This retrospective cross-sectional study utilized the National Patients Sample data from the 2017 Health Insurance Review and Assessment Service. We analyzed 16,950 patients with MDD, defined as those with at least two claims records stating a primary diagnosis of MDD (International Classification of Diseases, 10th revision codes F32-33) and 67,800 patients without MDD (1:4 propensity-score matched control group). Antibiotic use was compared between the patients with and without MDD based on three variables: the presence of antibiotic prescriptions, total prescription days of antibiotics per year, and total medication costs of antibiotics per year. RESULTS: The adjusted odds ratio obtained by multivariate regression analysis for the presence of prescription of antibiotics was 1.31 (95% confidence interval [CI]: 1.25-1.36). In the negative binomial model, the number of prescription days was 1.25 times (95% CI: 1.23-1.28) higher in patients with MDD than in those without MDD. Generalized linear model analysis showed a 1.39-fold (95% CI: 1.36-1.43) higher cost of antibiotic prescription in patients with MDD than in those without MDD. CONCLUSIONS: Our results suggest a potential association between MDD and the prescription of antibiotics, implying that patients with MDD are relatively vulnerable to infections. It is important to prevent as well as closely monitor the occurrence of infections when managing patients with MDD.

Newly designed Protein Transduction Domain (PTD)-mediated BMP-7 is a potential therapeutic for peritoneal fibrosis.

While the bone morphogenetic protein-7 (BMP-7) is a well-known therapeutic growth factor reverting many fibrotic diseases, including peritoneal fibrosis by peritoneal dialysis (PD), soluble growth factors are largely limited in clinical applications owing to their short half-life in clinical settings. Recently, we developed a novel drug delivery model using protein transduction domains (PTD) overcoming limitation of soluble recombinant proteins, including bone morphogenetic protein-7 (BMP-7). This study aims at evaluating the therapeutic effects of PTD-BMP-7 consisted of PTD and full-length BMP-7 on epithelial-mesenchymal transition (EMT)-related fibrosis. Human peritoneal mesothelial cells (HPMCs) were then treated with TGF-ß1 or TGF-ß1 + PTD-BMP-7. Peritoneal dialysis (PD) catheters were inserted into Sprague-Dawley rats, and these rats were infused intra-peritoneally with saline, peritoneal dialysis fluid (PDF) or PDF + PTD-BMP-7. In vitro, TGF-ß1 treatment significantly increased fibronectin, type I collagen, α-SMA and Snail expression, while reducing E-cadherin expression in HPMCs (P < .001). PTD-BMP-7 treatment ameliorated TGF-ß1-induced fibronectin, type I collagen, α-SMA and Snail expression, and restored E-cadherin expression in HPMCs (P < .001). In vivo, the expressions of EMT-related molecules and the thickness of the sub-mesothelial layer were significantly increased in the peritoneum of rats treated with PDF, and these changes were significantly abrogated by the intra-peritoneal administration of PTD-BMP-7. PTD-BMP-7 treatment significantly inhibited the progression of established PD fibrosis. These findings suggest that PTD-BMP-7, as a prodrug of BMP-7, can be an effective therapeutic agent for peritoneal fibrosis in PD patients.

Cost-utility analysis of pralatrexate for relapsed or refractory peripheral T-cell lymphoma based on a case-matched historical control study along with single arm clinical trial.

BACKGROUND: Patients with relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) treated with pralatrexate have previously shown superior overall survival (OS) compared to those who underwent conventional chemotherapy (CC, 15.4 vs. 4.07 months). We conducted an economic evaluation of pralatrexate from a societal perspective in Korea based on data from the PROPEL phase II study. METHODS: Using a Markov model with a weekly cycle, we simulated the experience of patients with R/R PTCL receiving pralatrexate or CC for 15 years. The model consists of five health states; initial treatment, treatment pause, subsequent treatment, stem cell transplantation (SCT) success, and death. Comparative effectiveness was based on PROPEL phase II single-arm study and its matched historical control analysis. Costs included drug, drug administration, monitoring, adverse event management, and SCT costs. RESULTS: The incremental cost-effectiveness ratio of the base case was $39,153 per quality-adjusted life-year (QALY) gained. The results of one-way sensitivity analysis ranged from $33,949 to $51,846 per QALY gained, which remained within an implicit willingness-to-pay (WTP) threshold of anticancer drugs in Korea. CONCLUSIONS: Pralatrexate is a cost-effective intervention with improved OS and incremental costs within the WTP limit. Pralatrexate could function as a new therapeutic option for patients suffering from life-threatening R/R PTCL.

Assessing the risk of type 2 diabetes mellitus among children and adolescents with psychiatric disorders treated with atypical antipsychotics: a population-based nested case-control study.

To examine the associations between atypical antipsychotic (AAP) exposure and the development of type 2 diabetes mellitus (T2DM) in Korean pediatric patients with psychiatric disorders, we conducted a nested case-control study using the claims data of the National Health Insurance system of Korea between 2010 and 2014. A cohort of patients with psychiatric disorders was identified, and enrollment was taken as the date of the first psychiatric diagnosis. Cases involved patients with a diagnosis of T2DM or prescriptions for glucose lowering drugs after enrollment, and the identification of T2DM was defined as the index date. We performed a conditional logistic regression analysis for matched case-control data to assess associations between AAP exposure and T2DM, and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) are presented. From 1,092,019 patients aged 2-19 years, we identified 20,263 cases with T2DM and 80,043 controls, matched by sex, age, enrollment date, and primary psychiatric diagnosis. After adjusting for comorbidities, psychotropic medication history, and the healthcare institution characteristics, the aOR of having T2DM was significantly higher in multi-AAP users compared with non-users (aOR 1.89; 95% CI 1.63-2.20). Particularly high ORs for T2DM were observed in clozapine users compared with non-users (aOR 3.47; 95% CI 1.88-6.41). We observed a linear relationship between the increase in risperidone dose and the increase in the risk of developing T2DM. Our findings suggest a significantly increased risk of developing T2DM in child or adolescent patients with psychiatric disorders exposed to AAPs compared with those not exposed to AAPs.

The locally activated renin-angiotensin system is involved in albumin permeability in glomerular endothelial cells under high glucose conditions.

Background: Although the diabetic milieu per se , hemodynamic changes, oxidative stress and local growth factors such as angiotensin II (AII) are considered to be mediators in the pathogenesis of diabetic nephropathy, the underlying pathways mediating the changes in glomerular endothelial cells (GECs) are not well understood. Therefore, we investigated changes in the renin-angiotensin system (RAS) components in high glucose (HG)-stimulated GECs and the role of the local RAS in morphological and functional changes in GECs under diabetic conditions. Methods: We stimulated GECs with 5.6 mM glucose or 30 mM glucose with or without an angiotensin II type I receptor blocker (ARB) in vitro and also performed experiments with Sprague-Dawley rats injected with diluent ( n = 16) or streptozotocin [ n = 16, diabetes (DM)]. Eight rats from each group were treated with ARB for 3 months in vivo . Real-time polymerase chain reaction, western blot analysis, enzyme-linked immunosorbent assay and immunofluorescent staining using cultured GECs were performed. The permeability of GECs to macromolecules was assessed by measuring the passage of fluorescein isothiocyanate-labeled bovine serum albumin. Morphological changes were also evaluated by scanning and transmission electron microscopy. Results: There were significant increases in angiotensinogen expression in HG-stimulated GECs along with significant increases in AI and AII levels. Moreover, the expression of heparan sulfate glycosaminoglycans (HS-GAG) assessed by immunofluorescent staining was significantly lower and the permeability to albumin was significantly higher in GECs exposed to HG medium, and ARB treatment significantly abrogated these changes. Upon electron microscopy examination, the mean size of the GEC fenestrae was significantly greater in HG-stimulated GECs and DM rats, and these increases were significantly ameliorated by ARB. Conclusions: The local RAS within GECs was activated under HG conditions, and this activation may be associated with both an alteration in GEC fenestration and a decrease in HS-GAG, resulting in the development of albuminuria in diabetic nephropathy.

Circulating CD89-IgA complex does not predict deterioration of kidney function in Korean patients with IgA nephropathy.

BACKGROUND: Soluble CD89 (sCD89)-IgA complex plays a key role in the pathogenesis of IgA nephropathy (IgAN). However, there is a lack of evidence supporting this complex as a good biomarker for disease progression. This study aimed to evaluate the usefulness of sCD89-IgA complex for risk stratification of IgAN. METHODS: A total of 326 patients with biopsy-proven IgAN were included. sCD89-IgA complex was measured by sandwich-enzyme-linked immunosorbent assay. The study endpoints were a 30% decline in estimated glomerular filtration rate (eGFR). RESULTS: sCD89-IgA complex levels were inversely and weakly associated with eGFR at the time of biopsy (r=-0.12, p=0.03). However, the significance between the two factors was lost in the multivariate linear regression after adjustment of clinical factors (ß=0.35, p=0.75). In a multivariate Cox model, the highest (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.35-1.61; p=0.45) and middle (HR, 0.93; 95% CI, 0.46-1.89; p=0.84) tertiles of sCD89-IgA complex levels were not associated with an increased risk of developing a 30% decrease in eGFR. Furthermore, the decline rates in eGFR did not differ between groups and C-statistics revealed that the sCD89-IgA complex were not superior to clinical factors in predicting disease progression. CONCLUSIONS: This study found no association between sCD89-IgA complex levels and disease progression in IgAN. Although sCD89 can contribute to the formation of immune complexes, our findings suggest that the sCD89-IgA level is not a good predictor of adverse outcomes and has limited clinical utility as a biomarker for risk stratification in IgAN.

Prevalence and socio-economic burden of heart failure in an aging society of South Korea.

BACKGROUND: Heart failure (HF) is one of the leading causes of morbidity and mortality in South Korea. With the rapidly aging population in the country, the prevalence of HF and its associated costs are expected to rise continuously. This study was carried out to estimate the prevalence and economic burden of HF in order to understand its impact on our society. METHODS: A prevalence-based, cost-of-illness study was conducted using the 2014 Health Insurance Review and Assessment Service-National Patients Sample (HIRA-NPS) data. Adult HF patients were defined as those aged ≥19 years who had at least one insurance claim record with a primary or secondary diagnosis of HF (ICD-10 codes of I11.0, I13.0, I13.2, and I50.x). The costs consist of direct costs (i.e., medical and non-medical costs) and indirect costs (i.e., productivity loss cost due to morbidity and premature death). Subgroup analyses were conducted by age group, history of HF hospitalization, and type of universal health security program enrolled in. RESULTS: A total of 475,019 adults were identified to have HF in 2014. The estimated prevalence rate of HF was 12.4 persons per 1,000 adults. According to the base cases and the extended definition of the cases, the annual economic burden of HF from a societal perspective ranges from USD 1,414.0 to 1,560.5 for individual patients, and from USD 752.8 million to 1,085.6 million for the country. A high percentage (68.5 %) of this socioeconomic burden consist of medical costs, followed by caregiver's cost (13.2 %), productivity loss costs due to premature death (10.8 %) and morbidity (4.2 %), and transportation costs (3.4 %). The HF patients with prior hospitalization due to HF annually spent 9.7 times more for National-Health-Insurance-covered medical costs compared to HF patients who were not previously hospitalized. CONCLUSIONS: In the present study, HF patients who were older and had a history of prior hospitalization for HF as well as an indigent status were shown at high risk of spending more for healthcare to treat their HF. An effective disease management protocol should be employed to target this patient group.

Double transduction of a Cre/LoxP lentiviral vector: a simple method to generate kidney cell-specific knockdown mice.

In a lentivirus-based gene delivery system, the incorporated gene is continuously expressed for a long time. In this study, we devised a simple way to knock down a specific gene in a kidney cell-specific pattern in adult mice by lentivirus-assisted transfer of short hairpin RNA (shRNA). Kidney collecting duct (CD)-specific aquaporin-3 (AQP3)-knockdown mice were generated by consecutive injection of Hoxb7-Cre-expressing lentivirus (LV-Hoxb7 Cre) and loxP-AQP3 shRNA-expressing lentivirus (LV-loxP shAQP3) in adult C57BL6/J mice. LV-Hoxb7 Cre was designed to express mCherry, while LV-loxP shAQP3 was designed with a floxed enhanced green fluorescent protein (EGFP)-tagged stop sequence, and thus EGFP would be expressed only in the absence of Cre recombination. In mice treated with LV-Hoxb7 Cre alone, mCherry protein expression, which indicates the presence of Cre recombinase, occurred only in CD cells. However, LV-loxP shAQP3 injection alone resulted in an increase in EGFP expression in all kidney cells, indicating the transcription of the floxed region. When LV-Hoxb7 Cre and LV-loxP shAQP3 were sequentially transduced, EGFP expression was attenuated while mCherry expression was sustained in CD cells, demonstrating a CD cell-specific recombination of the floxed region. AQP3 expression in mice injected with LV-Hoxb7 Cre or LV-loxP shAQP3 alone did not differ, but consecutive injection of LV-Hoxb7 Cre and LV-loxP shAQP3 significantly reduced AQP3 expression in CD cells. However, the expression levels of AQP3 were not altered in other cell types. Double transduction of Cre- and loxP-based lentivirus can easily generate kidney cell-specific knockdown mice, and this method might be applicable to other species.

Podocyte hypertrophy precedes apoptosis under experimental diabetic conditions.

Podocyte hypertrophy and apoptosis are two hallmarks of diabetic glomeruli, but the sequence in which these processes occur remains a matter of debate. Here we investigated the effects of inhibiting hypertrophy on apoptosis, and vice versa, in both podocytes and glomeruli, under diabetic conditions. Hypertrophy and apoptosis were inhibited using an epidermal growth factor receptor inhibitor (PKI 166) and a pan-caspase inhibitor (zAsp-DCB), respectively. We observed significant increases in the protein expression of p27, p21, phospho-eukaryotic elongation factor 4E-binding protein 1, and phospho-p70 S6 ribosomal protein kinase, in both cultured podocytes exposed to high-glucose (HG) medium, and streptozotocin-induced diabetes mellitus (DM) rat glomeruli. These increases were significantly inhibited by PKI 166, but not by zAsp-DCB. In addition, the amount of protein per cell, the relative cell size, and the glomerular volume were all significantly increased under diabetic conditions, and these changes were also blocked by treatment with PKI 166, but not zAsp-DCB. Increased protein expression of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase, together with increased Bax/Bcl-2 ratios, were also observed in HG-stimulated podocytes and DM glomeruli. Treatment with either zAsp-DCB or PKI 166 resulted in a significant attenuation of these effects. Both PKI 166 and zAsp-DCB also inhibited the increase in number of apoptotic cells, as assessed by Hoechst 33342 staining and TUNEL assay. Under diabetic conditions, inhibition of podocyte hypertrophy results in attenuated apoptosis, whereas blocking apoptosis has no effect on podocyte hypertrophy, suggesting that podocyte hypertrophy precedes apoptosis.

Enhanced glycogen synthase kinase-3ß activity mediates podocyte apoptosis under diabetic conditions.

Glycogen synthase kinase-3ß (GSK-3ß) is involved in the pathogenesis of various kidney diseases. This study was undertaken to examine the changes in GSK-3ß activity in podocytes under diabetic conditions and to elucidate the functional role of GSK-3ß in podocyte apoptosis. In vivo, 32 rats were injected with either diluent (n = 16, C) or with streptozotocin intraperitoneally (n = 16, DM), and 8 rats from each group were treated with 6-bromoindirubin-3'-oxime (BIO) for 3 months. In vitro, immortalized mouse podocytes were exposed to 5.6 mM glucose or 30 mM glucose (HG) with or without 10 µM BIO. Western blot analysis and TUNEL or Hoechst 33342 staining were performed to identify apoptosis. Urinary albumin excretion was significantly higher in DM rats, and this increase was significantly abrogated in DM rats by BIO treatment. The protein expression of Tyr216-phospho-GSK-3ß was significantly increased in DM glomeruli and in cultured podocytes exposed to HG. Western blot analysis revealed that the protein expression of Bax and active fragments of caspase-3 were significantly increased, whereas phospho-Akt, ß-catenin, and Bcl-2 protein expression were significantly decreased in DM glomeruli and HG-stimulated podocytes. Apoptosis, determined by TUNEL assay and Hoechst 33342 staining, was also significantly increased in podocytes under diabetic conditions. The changes in the expression of apoptosis-related molecules and the increase in the number of apoptotic cells in DM glomeruli as well as in HG-stimulated podocytes were significantly ameliorated by BIO. These findings suggest that enhanced GSK-3ß activity within podocytes under diabetic conditions is associated with podocyte loss in diabetic nephropathy.

Up-regulation of fibroblast growth factor (FGF) 9 expression and FGF-WNT/ß-catenin signaling in laser-induced wound healing.

Fibroblast growth factor (FGF) 9 is secreted by both mesothelial and epithelial cells, and plays important roles in organ development and wound healing via WNT/ß-catenin signaling. The aim of this study was to evaluate FGF9 expression and FGF-WNT/ß-catenin signaling during wound healing of the skin. We investigated FGF9 expression and FGF-WNT/ß-catenin signaling after laser ablation of mouse skin and adult human skin, as well as in cultured normal human epidermal keratinocytes (NHEKs) upon stimulation with recombinant human (rh) FGF9 and rh-transforming growth factor (TGF)-ß1. Our results showed that laser ablation of both mouse skin and human skin leads to marked overexpression of FGF9 and FGF9 mRNA. Control NHEKs constitutively expressed FGF9, WNT7b, WNT2, and ß-catenin, but did not show Snail or FGF receptor (FGFR) 2 expression. We also found that FGFR2 was significantly induced in NHEKs by rhFGF9 stimulation, and observed that FGFR2 expression was slightly up-regulated on particular days during the wound healing process after ablative laser therapy. Both WNT7b and WNT2 showed up-regulated protein expression during the laser-induced wound healing process in mouse skin; moreover, we discerned that the stimulatory effect of rhFGF9 and rhTGF-ß1 activates WNT/ß-catenin signaling via WNT7b in cultured NHEKs. Our data indicated that rhFGF9 and/or rhTGF-ß1 up-regulate FGFR2, WNT7b, and ß-catenin, but not FGF9 and Snail; pretreatment with rh dickkopf-1 significantly inhibited the up-regulation of FGFR2, WNT7b, and ß-catenin. Our results suggested that FGF9 and FGF-WNT/ß-catenin signaling may play important roles in ablative laser-induced wound healing processes.

Effect of health insurance type on health care utilization in patients with hypertension: a national health insurance database study in Korea.

BACKGROUND: Higher utilization of healthcare services has been observed among individuals who receive public aid compared to individuals who do not receive public aid in many countries. However, no systematic investigations have explored whether this pattern of higher utilization persists after correcting for a number of factors in Korea. In this study, we sought to examine whether the type of health insurance, wage-based contributory insurance (Health Insurance, HI) or government-subsidized public assistance (Medical Aid, MA), affects the utilization of inpatient services after controlling for baseline patient and institutional characteristics among patients with hypertension in Korea. METHODS: The Korean National Health Insurance claims database from 2006 and 2007 was used for analysis. To avoid biased estimates, we determined the most appropriate type of multivariate model for each outcome variable: a logistic regression model for the likelihood of hospitalization, a zero-inflated negative binomial model for the length of stay (LOS), and a generalized linear model with a log-link function for hospitalization costs. RESULTS: Adjusted odds ratio (OR) and factor changes showed that MA patients (n = 21,539) had a significantly higher likelihood of hospitalization (OR: 1.41-1.71), average LOS per patient (factor change: 1.31-1.42), and hospitalization costs per patient (factor change: 1.10-1.41) compared to HI patients (n = 304,027). CONCLUSIONS: The pattern of higher healthcare utilization among MA patients persists even after controlling for baseline health conditions. This finding confirms that the type of health insurance affects the utilization of healthcare resources, and suggests that effective strategies are necessary to prevent the potential overutilization of inpatient care by MA patients with hypertension in Korea.

Expert survey on real-world data utilization and real-world evidence generation for regulatory decision-making in drug lifecycle in Korea.

As the importance of utilizing real-world data (RWD)/real-world evidence (RWE) for supporting regulatory scientific decision-making continues to grow, experiences and inputs from experts become crucial for developing a systematic and practice-oriented plan for the use of fit-for-purpose RWD/RWE. This study aimed to survey relevant experts from government agencies, industries, and academia to identify prerequisites for the drug life cycle in Korea. The questionnaire comprised the following: (A) the definition and categories of RWD/RWE, (B) the suitability and feasibility of using RWD/RWE at each authorization stage by the types of RWD, and (C) the challenges and solutions for the use of RWD/RWE. A total of 46 respondents completed the online survey, with 89.1% of them having prior experience with RWD/RWE usage. A majority of respondents agreed that RWD can be obtained from various sources. Among these sources, the registry was the most suitable source. It is suitable to compensate for the limitations of randomized control trials and ensure quality in data collection. Though there was consensus among the respondents for the use of RWD/RWE in post-marketing surveillance, the use of such data in new drug application (NDA) was disagreeable. Respondents considered it necessary to write a protocol in advance for RWD collection and RWE generation, for all RWD types. In conclusion, this study examined the perceptions of experts for RWD/RWE use at each approval stage of drugs. The results suggest that guidelines for the fit-for-purpose use of RWD/RWE should be developed via careful deliberation among experts in the future.

Cost-Effectiveness Analysis of COMT-Inhibitors as Adjuvant Treatments to Levodopa in Patients with Advanced Parkinson's Disease.

PURPOSE: We aimed to elicit scientific evidence on the cost-effectiveness of two catechol-O-methyltransferase inhibitors (COMT-i) versus no COMT-i in patients with advanced Parkinson's disease. METHODS: A mixed model of the decision tree and a Markov model with three health states by OFF-time level (<25%, ≥25%, and death) was constructed to compare opicapone (OPC), entacapone (ENT), and no COMT-i over a lifetime. A hypothetical cohort of 10,000 patients was created and simulated based on the characteristics of the BIPARK trial subjects. FINDINGS: Two COMT-i (OPC and ENT) were identified as a cost-effective option compared to no COMT-i. Probabilistic sensitivity analysis showed that over 90% of the simulations proved the robust cost-effectiveness of COMT-i. When the time horizon as the most influential factor decreases to a 5- and 10-year period, COMT-i can be a cost-saving option. Although ENT may be the preferred option over OPC economically because of its lower price, OPC can be acceptable if the drug price is reduced by 17%. IMPLICATIONS: Add-on treatment with COMT-i in patients with PD receiving levodopa/carbidopa appears to be cost-saving compared with not using COMT-i. In the future, it is necessary to evaluate the economic evaluation of COMT-i based on long-term real-world evidence.

Effects of the coronavirus disease outbreak on the development of neurological disorders in children: A comparison of the incidence of febrile seizure and epilepsy using an interrupted time-series approach.

BACKGROUND: With the outbreak of COVID-19, school closures and quarantines following social distancing have brought significant changes to children's lifestyles. Therefore, we aimed to compare the population-adjusted incidence of febrile seizures(FS) and epilepsy before and after the COVID-19 outbreak in Korea and to assess the effects of the COVID-19 outbreak on the incidence by region and age group. METHODS: A retrospective cohort study was conducted using nationwide claims data and covid data from January 2019 to December 2020. The incidence of diseases and difference in incidence before (Jan 20 to Dec 30, 2019) and after (Jan 20 to Dec 30, 2020) the COVID-19 outbreak was measured using rate ratio. An Interrupted time series analysis was used to identify the effect of COVID-19 on trends of FS and epilepsy. Subgroup analysis by age, sex, insurance, and risk of coronavirus by area were conducted. RESULTS: Following the onset of the pandemic, the number of newly diagnosed FS cases decreased sharply by 69 % (24,182 to 7238), whereas the incidence of epilepsy, increased to 1.02 times (30,286-29,312), when adjusted in proportion to the population. Notably, a greater decrease in the incidence of FS were found in the regions with high-risk of coronavirus. A result of segmented regression analysis proved the decrease was significant and made immediately after the pandemic started(p < 0.001). In contrast to the incidence of FS, that of epilepsy did not exhibit a significant month-to-month change during the baseline period, immediately after the pandemic started, and during the pandemic. CONCLUSIONS: The COVID-19 outbreak and resulting social distancing measures reduced the incidence of febrile seizure immediately rather than gradually. Unlike in the case of acute febrile seizure, the COVID-19 pandemic had no effect on the incidence of chronic epilepsy.

Estimating the Incidence-Based Cost of Illness Due to Hematopoietic Stem Cell Transplantation Using One-Year Insurance Claim Data in Korea.

OBJECTIVES: Long-term follow-up data are required for incidence-based cost-of-illness (COI) studies, and it is difficult to carry out such assessments. To overcome this limitation, we estimated the acute and maintenance-state costs of hematopoietic stem cell transplantation (HSCT) using 1-year claim data. METHODS: Using Korean National Health Insurance (NHI) data from 2016, 2017, and 2018, we identified patients receiving HSCT based on the procedure code "X5*" (i.e., HSCT). The post-HSCT group was defined as patients without the "X5*" code, but with the code "Z948 (other transplanted conditions)" and indications of HSCT (referring to those who had received HSCT). Mean annual medical use and costs were computed using the monthly values available for each patient. RESULTS: The mean number of hospitalizations/year, outpatient visits per year, hospitalization days/year, and length of stay (LOS)/hospitalization were 8.14, 35.80, 97.16, and 14.72, respectively, for allogeneic HSCT patients (n = 56); 8.08, 33.58, 73.04, and 10.63, respectively, for autologous HSCT patients (n = 89); 2.93, 29.40, 50.95, and 20.84, respectively, for post-allogeneic HSCT patients (n = 40); and 1.72, 16.38, 30.11, and 19.29, respectively, for post-autologous HSCT patients (n = 252). The estimated annual NHI-covered medical costs (US dollars) were $38,833-$40,876 for the allogeneic HSCT group, $1749-$6744 for the post-allogeneic HSCT group, $21,231-$22,863 for the autologous HSCT group, and $3954-$5352 for the post-autologous HSCT group. CONCLUSIONS: This study describes an alternative method for conducting incidence-based COI studies using cross-sectional claims data.