Fibrates and risk of congenital malformations: a nationwide cohort study in South Korea.

PURPOSE: To examine the association between maternal prescriptions for fibrates and congenital malformations in live births. METHODS: Nationwide retrospective cohort study was conducted using the data sourced from the Korean National Health Insurance database. A cohort of 756,877 completed pregnancies linked to live-born infants in 215,600 women with dyslipidemia between 2012 and 2021. The study compared data on congenital anomalies between pregnancies who were exposed to fibrates and those who were not exposed to fibrates in the first trimester. Odds ratios (OR) were calculated by a multivariable analyses using logistic regression models to adjust for potential confounders. RESULTS: 260 pregnancies (0.12%) were exposed to fibrates during the first trimester. The prevalence of malformations in exposed offspirng was 10.77%, not significantly different compared with 9.68% in offspring of women who were not prescribed fibrates during pregnancy in patients with dyslipidemia (OR 1.13; 95% CI 0.75-1.70). CONCLUSION: This study implies that the use of fibrates during pregnancy may be safe, as it did not show any association with congenital anomalies. However, caution is warranted due to an elevated risk associated with prolonged exposure.

Exploring the influence of garlic on microbial diversity and metabolite dynamics during kimchi fermentation.

Garlic (Allium sativum) is a key ingredient in Korean cuisine, particularly in the preparation of kimchi, contributing to its flavor and taste. Garlic has been a potential resource for lactic acid bacteria (LAB) in kimchi. However, the mechanism by which it influences microbial diversity and metabolite production is unclear. This study investigated the effect of garlic on the bacterial composition of and metabolite changes in kimchi. To achieve this, four separate batches of kimchi were prepared with varying garlic concentrations (w/w): 0 %, 1 %, 2 %, and 4 %, and the bacterial communities and metabolite production were monitored. In the early stages of fermentation, the count of LAB, operational taxonomic units (OTUs), and Shannon index increased linearly with the increase in garlic content. This indicated that garlic is a rich resource and contributes to the diversity of LAB during kimchi fermentation. Compared with the kimchi samples with a lower garlic content, those with a high garlic content (≥2 %) exhibited increased abundance of Lactobacillus and Leuconostoc as well as noticeable differences in functional diversity, including carbohydrate, amino acid, and energy metabolisms. Correlation analysis between sugars, organic acids, and predominant LAB in the garlic-containing kimchi samples suggested that in kimchi samples with high garlic content, LAB played a significant role in the fermentation process by metabolizing sugars and producing organic acids. Overall, this study demonstrated that the addition of garlic has a positive impact on the bacterial diversity and metabolite production during kimchi fermentation, potentially affecting the fermentation process and flavor profile of kimchi.

Comparative Safety Analysis of Empagliflozin in Type 2 Diabetes Mellitus Patients with Chronic Kidney Disease versus Normal Kidney Function: A Nationwide Cohort Study in Korea.

BACKGROUND: Empagliflozin has been shown to reduce cardiovascular morbidity and mortality in patients with type 2 diabetes. Various research on its efficacy in patients with chronic kidney disease (CKD) have been actively conducted. So far, few studies have investigated the safety of these adverse effects specifically in Asians with CKD. We aim to address these safety concerns on a patient population of Asian CKD patients using real-world data. METHODS: We conducted a retrospective cohort study using health insurance data from the Korean Health Insurance Review & Assessment Service and compared safety outcomes between empagliflozin and sitagliptin in 26,347 CKD patients diagnosed with diabetes. Adverse outcomes, including major adverse cardiac events (MACEs), all-cause mortality, myocardial infarction (MI), stroke, and hospitalization for heart failure (HHF), among others, were assessed. RESULTS: Among a 1:1 matched cohort (6170 on empagliflozin, 6170 on sitagliptin), empagliflozin was associated with a significant reduction in MACEs, all-cause mortality, MI, hospitalization for unstable angina, coronary revascularization, HHF, hypoglycemic events, and urinary tract infections, but increased the risk of genital tract infections. No significant changes were observed for transient ischemic attack, acute kidney injury, volume depletion, diabetic ketoacidosis, thromboembolic events, and fractures. CONCLUSIONS: The usage of empagliflozin in diabetic CKD patients shows a significant reduction in many adverse outcomes compared to sitagliptin, but with an increased risk of genital tract infections. These findings provide evidence for future clinical decision-making around the use of empagliflozin in Asian CKD patients.

Clinical Effectiveness of Renal Transplant Outpatient Pharmaceutical Care Services in Korea.

BACKGROUND: The necessity and importance of pharmaceutical care services (PCS) are well recognized, yet the concept and scope of PCS have not yet been clearly defined in Korea, particularly in kidney transplantation outpatient clinics. AIM: The main purpose of this study is to evaluate whether PCS is effective in the outpatient setting for kidney transplant patients. METHODS: For three years, a clinical pharmacist provided PCS to kidney transplant patients in an outpatient setting to evaluate the clinical effectiveness of PCS. RESULTS: A total of 302 patients were matched in a 1:1 ratio, with 151 in the PCS group and 151 in the control group. These patients were followed, and a total of 476 interventions were provided to them, including medication reconciliation (n = 113, 23.7%), medication evaluation and management (n = 186, 39.1%), and pharmaceutical care transition (n = 177, 37.2%) services. The estimated glomerular filtration rate (eGFR) exhibited a notable difference between the control and PCS groups when comparing the pre- and post-study periods measurements. In the control group, there was a decline of 7.0 mL/min/1.73 m2 in eGFR. In contrast, the PCS group showed a smaller decline of 2.5 mL/min/1.73 m2 (p = 0.03). The adjusted odds ratio for end stage renal disease development in the PCS group was 0.51 (95% confidence interval: 0.26-0.96), indicating a significantly lower risk compared to the control group. CONCLUSION: Our study highlights the promising potential of PCS implementation in kidney transplantation outpatient clinics. Further research is needed to validate and expand upon these findings, especially in diverse clinical settings.

Transcriptional analysis of the molecular mechanism underlying the response of Lactiplantibacillus plantarum to lactic acid stress conditions.

Lactic acid bacteria (LAB) present various benefits to humans; they play key roles in the fermentation of food and as probiotics. Acidic conditions are common to both LAB in the intestinal tract as well as fermented foods. Lactiplantibacillus plantarum is a facultative homofermentative bacterium, and lactic acid is the end metabolite of glycolysis. To characterize how L. plantarum responds to lactic acid, we investigated its transcriptome following treatment with hydrochloride (HCl) or dl-lactic acid at an early stage of growth. Bacterial growth was more attenuated in the presence of lactic acid than in the presence of HCl at the same pH range. Bacterial transcriptome analysis showed that the expression of 67 genes was significantly altered (log2FC > 2 or < 2). A total of 31 genes were up- or downregulated under both conditions: 19 genes in the presence of HCl and 17 genes in the presence of dl-lactic acid. The fatty acid synthesis-related genes were upregulated in both acidic conditions, whereas the lactate racemization-related gene (lar) was only upregulated following treatment with dl-lactic acid. In particular, lar expression increased following l-lactic acid treatment but did not increase following HCl or d-lactic acid treatment. Expression of lar and production of d-lactic acid were investigated with malic and acetic acid; the results revealed a higher expression of lar and production of d-lactic acid in the presence of malic acid than that in the presence of acetic acid.

Isolation and Characterization of the Primary Marmoset (Callithrix jacchus) Retinal Pigment Epithelial Cells.

Marmosets have emerged as a valuable primate model in ophthalmic research due to their similarity to the human visual system and their potential for generating transgenic models to advance the development of therapies. In this study, we isolated and cultured primary retinal pigment epithelium (RPE) cells from marmosets to investigate the mechanisms underlying RPE dysfunction in aging and age-related macular degeneration (AMD). We confirmed that our culture conditions and materials supported the formation of RPE monolayers with functional tight junctions that closely resembled the in vivo RPE. Since serum has been shown to induce epithelial-mesenchymal transition (EMT) in RPE cells, we compared the effects of fetal bovine serum (FBS) with serum-free supplements B27 on transepithelial electrical resistance (TER), cell proliferation, and morphological characteristics. Additionally, we assessed the age-related morphological changes of in vivo and primary RPE cells. Our results indicate that primary marmoset RPE cells exhibit in vivo-like characteristics, while cells obtained from an older donor show evidence of aging, including a failure to form a polarized monolayer, low TER, and delayed cell cycle. In conclusion, our primary marmoset RPE cells provide a reliable in vitro model for developing novel therapeutics for visual-threatening disorders such as AMD, which can be used before animal experiments using marmosets.

Ultrasonographic monitoring of fetal eye growth parameters throughout gestation in the common marmoset (Callithrix jacchus).

The common marmoset (Callithrix jacchus) is considered an ideal species for developing genetically modified nonhuman primates (NHP) models of human disease, particularly eye disease. They have been proposed as a suitable bridge between rodents and other NHP models due to their similar ophthalmological features to humans. Prenatal ultrasonography is an accurate and reliable diagnostic tool for monitoring fetal development and congenital malformation. We monitored fetal eye growth and development using noninvasive ultrasonography in 40 heads of clinically normal fetuses during pregnancy to establish the criteria for studying congenital eye anomalies in marmosets. The coronal, sagittal, and transverse planes were useful to identify the facial structures for any associated abnormalities. For orbital measurements, biorbital distance (BOD), ocular diameter (OD), interorbital distance (IOD), and total axial length (TAL) were measured in the transverse plane and carefully identified for intraorbital structures. As a result, high correlations were observed between delivery-based gestational age (GA) and biparietal diameter (BPD), BOD, OD, and TAL. The correlation assessments based on BOD provide more reliable results for monitoring eye growth and development in normal marmosets than any other parameters since BOD has the highest correlation coefficient according to both delivery-based GA and BPD among ocular measurements. In conclusion, orbital measurements by prenatal ultrasonography provide reliable indicators of marmoset eye growth, and it could offer early diagnostic criteria to facilitate the development of eye disease models and novel therapies such as genome editing technologies in marmosets.

Elemental Analysis of Kimchi Cabbage Leaves, Roots, and Soil and Its Potential Impact on Human Health.

In view of their rich mineral content and flavor, kimchi cabbage leaves and roots have high nutritional and medicinal values. In this study, we quantified major nutrient (Ca, Cu, Fe, K, Mg, Na, and Zn), trace (B, Be, Bi, Co, Ga, Li, Ni, Se, Sr, V, and Cr), and toxic (Pb, Cd, Tl, and In) elements in kimchi cabbage cultivation soil, leaves, and roots. The analysis method relied on inductively coupled plasma-optical emission spectrometry for major nutrient elements and inductively coupled plasma-mass spectrometry for trace and toxic elements and complied with the Association of Official Analytical Chemists (AOAC) guidelines. Kimchi cabbage leaves and roots featured high contents of K, B, and Be, while the contents of all toxic elements in all samples were below the WHO-stipulated threshold values and therefore did not pose any health risks. The distribution of elements was characterized by heat map analysis and linear discriminant analysis to reveal independent separation according to the content of each element. The analysis confirmed that there was a difference in content between the groups and that each group was independently distributed. This study may contribute to a better understanding of the complex relationships between plant physiology, cultivation condition, and human health.

Klotho prevents transforming growth factor-ß2-induced senescent-like morphological changes in the retinal pigment epithelium.

Degenerative changes of the retinal pigment epithelium (RPE) triggered by transforming growth factor-ß2 (TGF-ß2) and oxidative stress play a critical role in the progression of age-related macular degeneration (AMD). The expression of α-klotho, an antiaging protein, declines with age, increasing the risk factors for age-related diseases. Here, we investigated the protective effects of soluble α-klotho on TGF-ß2-induced RPE degeneration. The morphological changes induced by TGF-ß2, including epithelial-mesenchymal transition (EMT), were attenuated in the mouse RPE by the intravitreal injection (IVT) of α-klotho. In ARPE19 cells, EMT and morphological alterations by TGF-ß2 were attenuated by co-incubation with α-klotho. TGF-ß2 decreased miR-200a accompanied by zinc finger e-box binding homeobox1 (ZEB1) upregulation and EMT, all of which were prevented by α-klotho co-treatment. Inhibitor of miR-200a mimicked TGF-ß2-induced morphological changes, which were recovered by ZEP1 silencing, but not by α-klotho, implying the upstream regulation of α-klotho on miR-200a-ZEP1-EMT axis. α-Klotho inhibited receptor binding of TGF-ß2, Smad2/3 phosphorylation, extracellular signal-regulated protein kinase 1/2 (ERK1/2)-a mechanistic target of rapamycin (mTOR) activation and oxidative stress via NADPH oxidase 4 (NOX4) upregulation. Furthermore, α-klotho recovered the TGF-ß2-induced mitochondrial activation and superoxide generation. Interestingly, TGF-ß2 upregulated α-klotho expression in the RPE cells, and genetic suppression of endogenous α-klotho aggravated TGF-ß2-induced oxidative stress and EMT. Lastly, α-klotho abrogated senescence-associated signaling molecules and phenotypes induced by long-term incubation with TGF-ß2. Hence, our findings indicate that the antiaging α-klotho plays a protective role against EMT and degeneration of the RPE, demonstrating the therapeutic potential for age-related retinal diseases, including the dry type of AMD.

Rapid Quantitative Analysis of Metabolites in Kimchi Using LC-Q-Orbitrap MS.

Kimchi is a traditional Korean salted spontaneous lactic acid bacteria (LAB)-fermented food made using various vegetables. Organic acids, free sugars, and amino acids are key metabolites produced during LAB fermentation that determine the taste and quality of kimchi. However, each metabolite is typically analyzed using an independent analytical method, which is time-consuming and expensive. Therefore, in this study, we developed a method based on LC-Q-Orbitrap MS using which 20 types of representative fermented kimchi metabolites were selected and simultaneously analyzed within 10 min. The established method was validated, and its detection and quantification limits, linearity, precision, and accuracy were found to satisfy the Association of Official Agricultural Chemists (AOAC) validation guidelines. The 20 metabolites were simultaneously extracted from kimchi with different degrees of fermentation and quantitatively analyzed using LC-Q-Orbitrap MS. These results were analyzed using linear discriminant analysis and heat mapping, and the metabolites were grouped into early, middle, and late stages of fermentation. Malic acid (6.518-7.701 mMol) was only present in the initial stage of fermentation, and l-phenylalanine rapidly increased from the middle stage (2.180 mMol) to late stage (4.770 mMol). Lactic acid, which is representative of the sour taste of kimchi, was detected in the middle stage and increased rapidly up to 74.452 mMol in the late stage. In summary, in this study, 20 major kimchi metabolites were accurately analyzed within 10 min and grouped based on the degree of fermentation. Therefore, the method established in this study accurately and rapidly provides information on kimchi consumption and fermentation that could be highly valuable to the kimchi industry and kimchi consumers.

Drug repurposing using meta-analysis of gene expression in Alzheimer's disease.

Introduction: Alzheimer's disease and other forms of dementia are disease that bring an increased global burden. However, the medicine developed to date remains limited. The purpose of this study is to predict drug repositioning candidates using a computational method that integrates gene expression profiles on Alzheimer's disease and compound-induced changes in gene expression levels. Methods: Gene expression data on Alzheimer's disease were obtained from the Gene Expression Omnibus (GEO) and we conducted a meta-analysis of their gene expression levels. The reverse scores of compound-induced gene expressions were computed based on the reversal relationship between disease and drug gene expression profiles. Results: Reversal genes and the candidate compounds were identified by the leave-one-out cross-validation procedure. Additionally, the half-maximal inhibitory concentration (IC50) values and the blood-brain barrier (BBB) permeability of candidate compounds were obtained from ChEMBL and PubChem, respectively. Conclusion: New therapeutic target genes and drug candidates against Alzheimer's disease were identified by means of drug repositioning.

Carfilzomib's Real-World Safety Outcomes in Korea: Target Trial Emulation Study Using Electronic Health Records.

Carfilzomib is a promising anticancer drug for relapsed/refractory multiple myeloma (RRMM). However, real-world evidence has only investigated the cardiovascular safety of carfilzomib, and there is a high demand for thorough safety evaluations. We aimed to comprehensively evaluate the risk of adverse events associated with carfilzomib in Korean patients with RRMM. We followed up with 138 matched patients with RRMM (69 KRd (carfilzomib, lenalidomide, and dexamethasone) and 69 Rd (lenalidomide and dexamethasone) users). A total of 12 adverse events were evaluated. More than 75% of adverse events occurred during the early cycle (1-6 cycles), and the incidence rate showed a tendency to decrease in the later cycle (7-12 and 13-18 cycles). Severities of most adverse events were evaluated as grade 1-2. The KRd regimen were related with significantly increased risks of dyspnea (adjusted HR (aHR) 2.27, 95% confidence interval (CI) 1.24-4.16), muscle spasm (aHR 5.12, 95% CI 1.05-24.9) and thrombocytopenia (aHR 1.84, 95% CI 1.10-3.06). Although the severities were low, carfilzomib has many side effects in treating RRMM; hence, findings on the patterns of its adverse events could lead to both effective and safe use of KRd therapy in real-world settings.

Using real-world data for supporting regulatory decision making: Comparison of cardiovascular and safety outcomes of an empagliflozin randomized clinical trial versus real-world data.

Aims: In countries where a randomized clinical trial (RCT) is difficult to perform, a real-world evidence (RWE) study with a design similar to an RCT may be an option for drug regulatory decision-making. In this study, the objective was to find out to what extent the safety of empagliflozin from the RWE study in Korea is different from the one in RCT by emulating the design of foreign RCT. The outcome covers various safety outcomes including cardiovascular safety. Methods: The EMPA-REG OUTCOME trial (NCT01131676) was selected for comparison. The inclusion/exclusion criteria and follow-up method for the RWE were matched to the comparison RCT. Major adverse cardiovascular events (MACEs) were used as a primary outcome and 15 other outcomes were also included for analysis. Result: We followed 23,126 matched patients with type 2 diabetes mellitus (11,563 empagliflozin users and 11,563 sitagliptin users) for 2.7 years (median). Empagliflozin use was associated with a significantly decreased risk of MACEs [EMPA-REG DUPLICATE RWE: adjusted HR 0.87, 95% confidence interval (CI) 0.79-0.96]. The predefined estimate agreement, regulatory agreement, and standardized difference for RCT duplication were achieved [EMPA-REG OUTCOME RCT: adjusted HR 0.86, 95% (CI) 0.74-0.99]. According to the predefined criteria for 15 outcomes, 10 outcomes were evaluated as good, and three as moderate. Conclusion: Our study results suggest that RWE in one country in comparison with an RCT has the potential for providing evidence for future regulatory decision-making in an environment where RCT could not be performed.

Machine learning-based quantitative prediction of drug exposure in drug-drug interactions using drug label information.

Many machine learning techniques provide a simple prediction for drug-drug interactions (DDIs). However, a systematically constructed database with pharmacokinetic (PK) DDI information does not exist, nor is there a machine learning model that numerically predicts PK fold change (FC) with it. Therefore, we propose a PK DDI prediction (PK-DDIP) model for quantitative DDI prediction with high accuracy, while constructing a highly reliable PK-DDI database. Reliable information of 3,627 PK DDIs was constructed from 3,587 drugs using 38,711 Food and Drug Administration (FDA) drug labels. This PK-DDIP model predicted the FC of the area under the time-concentration curve (AUC) within ± 0.5959. The prediction proportions within 0.8-1.25-fold, 0.67-1.5-fold, and 0.5-2-fold of the AUC were 75.77, 86.68, and 94.76%, respectively. Two external validations confirmed good prediction performance for newly updated FDA labels and FC from patients'. This model enables potential DDI evaluation before clinical trials, which will save time and cost.

CsRCI2D enhances high-temperature stress tolerance in Camelina sativa L. through endo-membrane trafficking from the plasma membrane.

Rare Cold Inducible 2s (RCI2s) are hydrophobic proteins in cell membranes that participate in abiotic stress tolerance mechanisms. Additionally, they are used as traceable membrane trafficking markers in endocytosis studies. Plants regulate cell homeostasis through endocytosis by limiting the activity of plasma membrane transporter proteins to adapt to stressful conditions. In this study, we found high temperature (HT) stress-induced membrane trafficking of RCI2D in Camelina sativa L. The gene expression and protein synthesis were increased by HT stress at 37 °C. Moreover, rapid membrane trafficking of CsRCI2D was traced by multiple-phase membrane fractionation using sucrose density gradients and compared with CsRCI2E/F/G from the same protein family subgroup. The distribution of CsRCI2s was shown to be similar to that of the clathrin heavy chain, which is known as a major endocytosis protein. Subcellular localization of CsRCI2D was observed in the plasma membrane and endo-membranes and overlapped with membrane lipids. CsRCI2D co-localized with lipids, and its overexpression increased the intracellular lipid content compared to that of wild-type camelina. Moreover, transgenic camelina lines showed enhanced HT stress tolerance during germination and hypocotyl elongation when compared to the wild type. These results suggest that HT-induced CsRCI2D membrane trafficking enhances HT stress tolerance in camelina.

Cysteinyl Leukotriene Receptor Antagonists Associated With a Decreased Incidence of Cancer: A Retrospective Cohort Study.

Aim: Cysteinyl leukotrienes receptor antagonists (LTRAs) are promising chemoprevention options to target cysteinyl leukotriene signaling in cancer. However, only a number of randomized clinical trials (RCTs) or observational studies have been conducted to date; thus, the effect of LTRAs on patients is yet to be elucidated. Using insurance claim data, we aimed to evaluate whether LTRAs have cancer preventive effects by observing patients who took LTRAs. Method: Patients diagnosed with asthma, allergic rhinitis, chronic cough, and have no history of cancer were followed-up from 2005 to 2017. Cox proportional hazard regression analysis was conducted to estimate the hazard ratios (HRs) for cancer risk of LTRA users. Result: We followed-up (median: 5.6 years) 188,906 matched patients (94,453 LTRA users and 94,453 non-users). LTRA use was associated with a decreased risk of cancer (adjusted HR [aHR] = 0.85, 95% confidence interval [CI] = 0.83-0.87). The cancer risk showed a tendency to decrease rapidly when LTRAs were used in high dose (aHR = 0.56, 95% CI = 0.40-0.79) or for longer durations of more than 3 years (aHR = 0.68, 95% CI = 0.60-0.76) and 5 years (aHR = 0.33, 95% CI = 0.26-0.42). The greater preventive effects of LTRAs were also observed in patients with specific risk factors related to sex, age, smoking, and the presence of comorbidities. Conclusion: In this study, we found that LTRA use was associated with a decreased risk of cancer. The high dose and long duration of the use of LTRAs correlated with a lower cancer risk. Since LTRAs are not yet used for the prevention or treatment of cancer, our findings could be used for developing a new chemo-regimen or designing feasible RCTs.

Self-Plugging Microneedle (SPM) for Intravitreal Drug Delivery.

Intravitreal injection (IVI) is a common technology which is used to treat ophthalmic diseases inside eyeballs by delivering various drugs into the vitreous cavity using hypodermic needles. However, in some cases, there are possible side effects such as ocular tissue damage due to repeated injection or eyeball infection through the hole created during the needle retraction process. The best scenario of IVI is a one-time injection of drugs without needle retraction, keeping the system of the eyeball closed. Microneedles (MNs) have been applied to ocular tissues over 10 years, and no serious side effects on ocular tissue due to MN injection have been reported. Therefore, a self-plugging MN (SPM) is developed to perform intraocular drug delivery and to seal the scleral puncture simultaneously. The SPMs are fabricated by a thermal drawing process and then coated with a polymeric carrier of drugs and a hydrogel-based scleral plugging component. Each coated functional layer is characterized and demonstrated by in vitro and ex vivo experiments. Finally, in vivo tests using a porcine model confirms prompt sealing of SPM and sustained intraocular drug delivery.

Effectiveness of Clinical Pharmacist Service on Drug-Related Problems and Patient Outcomes for Hospitalized Patients with Chronic Kidney Disease: A Randomized Controlled Trial.

(1) Background: The study aimed to analyze the effectiveness of clinical pharmacist services on drug-related problems (DRPs) and patient outcomes in inpatients with chronic kidney disease (CKD). (2) Methods: In a randomized controlled trial, the participants in the intervention group received pharmacist services, including medication reconciliation, medication evaluation and management, and discharge pharmaceutical care transition services. Participants in the control group received usual care. The primary outcome was the number of DRPs per patient at discharge. (3) Results: The baseline characteristics of 100 participants included the following: mean age, 52.5 years; median eGFR, 9.2 mL/min/1.73 m2. The number of DRPs in the intervention group during hospitalization increased significantly with decreasing eGFR (PR, 0.970; 95% CI, 0.951-0.989) and an increasing number of unintentional medication discrepancies at admission (PR, 1.294; 95% CI, 1.034-1.620). At discharge, the number of DRPs per patient was 0.94 ± 1.03 and 1.96 ± 1.25 in the intervention and control groups, respectively (p < 0.001). The service had a significant effect on the reduction of the unintentional discrepancies at discharge (p < 0.001). (4) Conclusion: Hospital pharmacists play an important role in the prevention of DRPs at discharge and unintentional medication discrepancies in inpatients with CKD.

Antidepressant Use and the Risk of Major Adverse Cardiovascular Events in Patients Without Known Cardiovascular Disease: A Retrospective Cohort Study.

Aims: Conflicting data exist on whether an association exists between antidepressants and the risk of major adverse cardiovascular events (MACEs) in patients with depression. This may be due to the use of various study designs and residual or unmeasured confounding. We aimed to assess the association between antidepressant use and the risk of MACEs while considering various covariates, including severity of depression and the cardiovascular disease (CVD) risk score. Methods: Patients newly diagnosed with depression with no history of ischemic heart disease and stroke were followed-up from 2009 to 2015. We conducted Cox proportional hazard regression analysis to estimate hazard ratios (HRs) for each antidepressant for MACE risk. Result: We followed-up (median, 4.4 years) 31,830 matched patients with depression (15,915 antidepressant users and 15,915 non-users). In most patients (98.7%), low-dose tricyclic antidepressants (TCAs) were related with a significantly increased risk of MACEs [adjusted HR = 1.20, 95% confidence interval (CI) = 1.03-1.40]. Duration response relationship showed a gradually increasing HR from 1.15 (95% CI = 0.98-1.33; <30 days of use) to 1.84 (95% CI = 1.35-2.51; ≥365 days of use) (p for trend <0.01). High Korean atherosclerotic CVD risk score (≥7.5%) or unfavorable lifestyle factors (smoking, alcohol intake, and exercise) were significantly associated with MACEs. Conclusion: Even at low doses, TCA use was associated with MACEs during primary prevention. Longer duration of TCA use correlated with higher HR. Careful monitoring is needed with TCA use in patients with no known CVD history.

Activation of ERK1/2-mTORC1-NOX4 mediates TGF-ß1-induced epithelial-mesenchymal transition and fibrosis in retinal pigment epithelial cells.

Transforming growth factor-ß (TGF-ß) plays a crucial role in the development of epithelial to mesenchymal transition (EMT) and fibrosis, particularly in an ocular disorder such as proliferative vitreoretinopathy (PVR). However, the key molecular mechanism underlying its pathogenesis remains unknown. In the present study, using cultured ARPE-19 cells, we determined that TGF-ß initiates a signaling pathway through extracellular signal-regulated kinase (ERK)-mammalian target of rapamycin complex 1 (mTORC1) that stimulates trans-differentiation and fibrosis of retinal pigment epithelium. Blocking this pathway by a TGF-ßRI, ERK or mTORC1 inhibitor protected cells from EMT and fibrotic protein expression. TGF-ß1 treatment increased reactive oxygen species (ROS) via NOX4 upregulation, which acts downstream of ERK and mTORC1, as the ROS scavenger N-acetylcysteine and a pan-NADPH oxidase (NOX) inhibitor DPI dissipated excess ROS generation. TGF-ß1-induced oxidative stress resulted in EMT and fibrotic changes, as NAC and DPI prevented α-SMA, Col4α3 expression and cell migration. All these inhibitors blocked the downstream pathway activation in addition to clearly preventing the activation of its upstream molecules, indicating the presence of a feedback loop system that may boost the upstream events. Furthermore, the FDA-approved drug trametinib (10 nM) blunted TGF-ß1-induced mTORC1 activation and downstream pathogenic alterations through ERK1/2 inhibition, which opens a therapeutic avenue for the treatment of PVR in the future.