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PURPOSE: This study aimed to advance the MetaLAB algorithm and verify its performance with multicenter data to effectively detect major adverse drug reactions (ADRs), including drug-induced liver injury. METHODS: Based on MetaLAB, we created an optimal scenario for detecting ADRs by considering demographic and clinical records. MetaLAB-HOI was developed to identify ADR signals using common model-based multicenter electronic health record (EHR) data from the clinical health outcomes of interest (HOI) template and design for drug-exposed and nonexposed groups. In this study, we calculated the odds ratio of 101 drugs for HOI in Konyang University Hospital, Seoul National University Hospital, Chungbuk National University Hospital, and Seoul National University Bundang Hospital. RESULTS: The overlapping drugs in four medical centers are amlodipine, aspirin, bisoprolol, carvedilol, clopidogrel, clozapine, digoxin, diltiazem, methotrexate, and rosuvastatin. We developed MetaLAB-HOI, an algorithm that can detect ADRs more efficiently using EHR. We compared the detection results of four medical centers, with drug-induced liver injuries as representative ADRs. CONCLUSIONS: MetaLAB-HOI's strength lies in fully utilizing the patient's clinical information, such as prescription, procedure, and laboratory results, to detect ADR signals. Considering changes in the patient's condition over time, we created an algorithm based on a scenario that accounted for each drug exposure and onset period supervised by specialists for HOI. We determined that when a template capable of detecting ADR based on clinical evidence is developed and manualized, it can be applied in medical centers for new drugs with insufficient data.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Sistemas de Registro de Reacción Adversa a Medicamentos , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Registros Electrónicos de Salud , Hospitales Universitarios , Evaluación de Resultado en la Atención de Salud , Estudios Multicéntricos como AsuntoRESUMEN
The premature death and degeneration of striatal neurons are typical hallmarks of HtrA2-inactivated motor neuron degeneration 2 (mnd2) mice. Although HtrA2 has been extensively studied in relation to the regulation of apoptosis using mnd2 mice, little is known about the other physiological functions of HtrA2. In this study, we found that the skin color of wild-type (WT) and mnd2 mice was black and pink on postnatal day 32. Using histological and molecular assays (i.e., assessing the activation of MAPK and expression patterns of PCNA), we demonstrated that this differential skin color change is consistent with the delay in the telogen - to - anagen phase of the hair cycle in mnd2 mice. We also examined adipocytes in the subcutaneous skin layer, finding that HtrA2 inactivation leads to the growth retardation of adipocytes, thereby delaying the hair cycle of mnd2 mice. Collectively, these findings show for the first time that HtrA2 plays an essential role in regulating the adipogenesis-associated hair cycle.
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Proteínas Mitocondriales , Serina Endopeptidasas , Animales , Ratones , Apoptosis , Cabello/metabolismo , Serina Peptidasa A2 que Requiere Temperaturas Altas/genética , Proteínas Mitocondriales/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismoRESUMEN
BACKGROUND: Pharmacovigilance using real-world data (RWD), such as multicenter electronic health records (EHRs), yields massively parallel adverse drug reaction (ADR) signals. However, proper validation of computationally detected ADR signals is not possible due to the lack of a reference standard for positive and negative associations. OBJECTIVE: This study aimed to develop a reference standard for ADR (RS-ADR) to streamline the systematic detection, assessment, and understanding of almost all drug-ADR associations suggested by RWD analyses. METHODS: We integrated well-known reference sets for drug-ADR pairs, including Side Effect Resource, Observational Medical Outcomes Partnership, and EU-ADR. We created a pharmacovigilance dictionary using controlled vocabularies and systematically annotated EHR data. Drug-ADR associations computed from MetaLAB and MetaNurse analyses of multicenter EHRs and extracted from the Food and Drug Administration Adverse Event Reporting System were integrated as "empirically determined" positive and negative reference sets by means of cross-validation between institutions. RESULTS: The RS-ADR consisted of 1344 drugs, 4485 ADRs, and 6,027,840 drug-ADR pairs with positive and negative consensus votes as pharmacovigilance reference sets. After the curation of the initial version of RS-ADR, novel ADR signals such as "famotidine-hepatic function abnormal" were detected and reasonably validated by RS-ADR. Although the validation of the entire reference standard is challenging, especially with this initial version, the reference standard will improve as more RWD participate in the consensus voting with advanced pharmacovigilance dictionaries and analytic algorithms. One can check if a drug-ADR pair has been reported by our web-based search interface for RS-ADRs. CONCLUSIONS: RS-ADRs enriched with the pharmacovigilance dictionary, ADR knowledge, and real-world evidence from EHRs may streamline the systematic detection, evaluation, and causality assessment of computationally detected ADR signals.
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Sistemas de Registro de Reacción Adversa a Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Famotidina , Humanos , Farmacovigilancia , Estándares de ReferenciaRESUMEN
Orbital fibroblasts (OFs) in thyroid-associated ophthalmopathy (TAO) are differentiated from pre-adipocytes and mature adipocytes; increased lipid and fat expansion are the major characteristics of ophthalmic manifestations. Human placental mesenchymal stem cells (hPMSCs) were reported to immunomodulate pathogenesis and suppress adipogenesis in TAO OFs. Here, we prepared transforming growth factor ß (TGFß, 20 ng/mL)-treated hPMSCs (TGFß-hPMSCs) in order to enhance anti-adipogenic effects in vitro and in TAO mice. TAO OFs were grown in a differentiation medium and then co-cultured with hPMSCs or TGFß-hPMSCs. TAO OFs were analyzed via quantitative real-time polymerase chain reaction, Oil red O staining, and western blotting. The results showed that TGFß-hPMSCs reduced the expression of adipogenic, lipogenic, and fibrotic genes better than hPMSCs in TAO OFs. Moreover, the adipose area decreased more in TAO mice injected with TGFß-hPMSCs compared to those injected with hPMSCs or a steroid. Further, TGFß-hPMSCs inhibited inflammation as effectively as a steroid. In conclusion, TGFß-hPMSCs suppressed adipogenesis and lipogenesis in vitro and in TAO mice, and the effects were mediated by the SMAD 2/3 pathways. Furthermore, TGFß-hPMSCs exhibited anti-inflammatory and anti-fibrotic functions, which suggests that they could be a new and safe method to promote the anti-adipogenic function of hPMSCs to treat TAO patients.
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Oftalmopatía de Graves , Células Madre Mesenquimatosas , Adipogénesis , Animales , Femenino , Oftalmopatía de Graves/patología , Humanos , Células Madre Mesenquimatosas/metabolismo , Ratones , Placenta/metabolismo , Embarazo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Adverse drug reactions (ADRs) are regarded as a major cause of death and a major contributor to public health costs. For the active surveillance of drug safety, the use of real-world data and real-world evidence as part of the overall pharmacovigilance process is important. In this regard, many studies apply the data-driven approaches to support pharmacovigilance. We developed a pharmacovigilance data-processing pipeline (PDP) that utilized electronic health records (EHR) and spontaneous reporting system (SRS) data to explore pharmacovigilance signals. METHODS: To this end, we integrated two medical data sources: Konyang University Hospital (KYUH) EHR and the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). As part of the presented PDP, we converted EHR data on the Observation Medical Outcomes Partnership (OMOP) data model. To evaluate the ability of using the proposed PDP for pharmacovigilance purposes, we performed a statistical validation using drugs that induce ear disorders. RESULTS: To validate the presented PDP, we extracted six drugs from the EHR that were significantly involved in ADRs causing ear disorders: nortriptyline, (hazard ratio [HR] 8.06, 95% CI 2.41-26.91); metoclopramide (HR 3.35, 95% CI 3.01-3.74); doxycycline (HR 1.73, 95% CI 1.14-2.62); digoxin (HR 1.60, 95% CI 1.08-2.38); acetaminophen (HR 1.59, 95% CI 1.47-1.72); and sucralfate (HR 1.21, 95% CI 1.06-1.38). In FAERS, the strongest associations were found for nortriptyline (reporting odds ratio [ROR] 1.94, 95% CI 1.73-2.16), sucralfate (ROR 1.22, 95% CI 1.01-1.45), doxycycline (ROR 1.30, 95% CI 1.20-1.40), and hydroxyzine (ROR 1.17, 95% CI 1.06-1.29). We confirmed the results in a meta-analysis using random and fixed models for doxycycline, hydroxyzine, metoclopramide, nortriptyline, and sucralfate. CONCLUSIONS: The proposed PDP could support active surveillance and the strengthening of potential ADR signals via real-world data sources. In addition, the PDP was able to generate real-world evidence for drug safety.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Farmacovigilancia , Sistemas de Registro de Reacción Adversa a Medicamentos , Bases de Datos Factuales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Humanos , Estados Unidos , Espera VigilanteRESUMEN
Human pluripotent stem cell-derived neural progenitor cells (NPCs) have the potential to recover from nerve injury. We previously reported that human placenta-derived mesenchymal stem cells (PSCs) have neuroprotective effects. To evaluate the potential benefit of NPCs, we compared them to PSCs using R28 cells under hypoxic conditions and a rat model of optic nerve injury. NPCs and PSCs (2 × 106 cells) were injected into the subtenon space. After 1, 2, and 4 weeks, we examined changes in target proteins in the retina and optic nerve. NPCs significantly induced vascular endothelial growth factor (Vegf) compared to age-matched shams and PSC groups at 2 weeks; they also induced neurofilaments in the retina compared to the sham group at 4 weeks. In addition, the expression of brain-derived neurotrophic factor (Bdnf) was high in the retina in the NPC group at 2 weeks, while expression in the optic nerve was high in both the NPC and PSC groups. The low expression of ionized calcium-binding adapter molecule 1 (Iba1) in the retina had recovered at 2 weeks after NPC injection and at 4 weeks after PSC injection. The expression of the inflammatory protein NLR family, pyrin domain containing 3 (Nlrp3) was significantly reduced at 1 week, and that of tumor necrosis factor-α (Tnf-α) in the optic nerves of the NPC group was lower at 2 weeks. Regarding retinal ganglion cells, the expressions of Brn3a and Tuj1 in the retina were enhanced in the NPC group compared to sham controls at 4 weeks. NPC injections increased Gap43 expression from 2 weeks and reduced Iba1 expression in the optic nerves during the recovery period. In addition, R28 cells exposed to hypoxic conditions showed increased cell survival when cocultured with NPCs compared to PSCs. Both Wnt/ß-catenin signaling and increased Nf-ĸb could contribute to the rescue of damaged retinal ganglion cells via upregulation of neuroprotective factors, microglial engagement, and anti-inflammatory regulation by NPCs. This study suggests that NPCs could be useful for the cellular treatment of various optic neuropathies, together with cell therapy using mesenchymal stem cells.
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Células-Madre Neurales/trasplante , Enfermedades del Nervio Óptico/terapia , Traumatismos del Nervio Óptico/terapia , Nervio Óptico/crecimiento & desarrollo , Células Madre Pluripotentes/trasplante , Animales , Axones/metabolismo , Axones/fisiología , Supervivencia Celular/genética , Tratamiento Basado en Trasplante de Células y Tejidos , Modelos Animales de Enfermedad , Femenino , Humanos , Regeneración Nerviosa/genética , Nervio Óptico/patología , Nervio Óptico/trasplante , Enfermedades del Nervio Óptico/patología , Embarazo , Ratas , Células Ganglionares de la Retina/trasplanteRESUMEN
Background: Acute kidney injury (AKI) is a marker of clinical deterioration and renal toxicity. While there are many studies offering prediction models for the early detection of AKI, those predicting AKI occurrence using distributed research network (DRN)-based time series data are rare. Objective: In this study, we aimed to detect the early occurrence of AKI by applying an interpretable long short-term memory (LSTM)-based model to hospital electronic health record (EHR)-based time series data in patients who took nephrotoxic drugs using a DRN. Methods: We conducted a multi-institutional retrospective cohort study of data from 6 hospitals using a DRN. For each institution, a patient-based data set was constructed using 5 drugs for AKI, and an interpretable multivariable LSTM (IMV-LSTM) model was used for training. This study used propensity score matching to mitigate differences in demographics and clinical characteristics. Additionally, the temporal attention values of the AKI prediction model's contribution variables were demonstrated for each institution and drug, with differences in highly important feature distributions between the case and control data confirmed using 1-way ANOVA. Results: This study analyzed 8643 and 31,012 patients with and without AKI, respectively, across 6 hospitals. When analyzing the distribution of AKI onset, vancomycin showed an earlier onset (median 12, IQR 5-25 days), and acyclovir was the slowest compared to the other drugs (median 23, IQR 10-41 days). Our temporal deep learning model for AKI prediction performed well for most drugs. Acyclovir had the highest average area under the receiver operating characteristic curve score per drug (0.94), followed by acetaminophen (0.93), vancomycin (0.92), naproxen (0.90), and celecoxib (0.89). Based on the temporal attention values of the variables in the AKI prediction model, verified lymphocytes and calcvancomycin ium had the highest attention, whereas lymphocytes, albumin, and hemoglobin tended to decrease over time, and urine pH and prothrombin time tended to increase. Conclusions: Early surveillance of AKI outbreaks can be achieved by applying an IMV-LSTM based on time series data through an EHR-based DRN. This approach can help identify risk factors and enable early detection of adverse drug reactions when prescribing drugs that cause renal toxicity before AKI occurs.
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Axonal degeneration resulting from optic nerve damage can lead to the progressive death of retinal ganglion cells (RGCs), culminating in irreversible vision loss. We contrasted two methods for inducing optic nerve damage: optic nerve compression (ONCo) and optic nerve crush (ONCr). These were assessed for their respective merits in simulating traumatic optic neuropathies and neurodegeneration. We also administered neural progenitor cells (NPCs) into the subtenon space to validate their potential in mitigating optic nerve damage. Our findings indicate that both ONCo and ONCr successfully induced optic nerve damage, as shown by increases in ischemia and expression of genes linked to neuronal regeneration. Post NPC injection, recovery in the expression of neuronal regeneration-related genes was more pronounced in the ONCo model than in the ONCr model, while inflammation-related gene expression saw a better recovery in ONCr. In addition, the proteomic analysis of R28 cells in hypoxic conditions identified Vps35 and Syntaxin12 genes. Vps35 preserved the mitochondrial function in ONCo, while Syntaxin12 appeared to restrain inflammation via the Wnt/ß-catenin signaling pathway in ONCr. NPCs managed to restore damaged RGCs by elevating neuroprotection factors and controlling inflammation through mitochondrial homeostasis and Wnt/ß-catenin signaling in hypoxia-injured R28 cells and in both animal models. Our results suggest that ischemic injury and crush injury cause optic nerve damage via different mechanisms, which can be effectively simulated using ONCo and ONCr, respectively. Moreover, cell-based therapies such as NPCs may offer promising avenues for treating various optic neuropathies, including ischemic and crush injuries.
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Traumatismos del Nervio Óptico , Animales , Axones/metabolismo , Inflamación/metabolismo , Regeneración Nerviosa/genética , Regeneración Nerviosa/fisiología , Neuroprotección/genética , Neuroprotección/fisiología , Traumatismos del Nervio Óptico/genética , Proteómica , Células Ganglionares de la Retina/metabolismo , Células Madre/metabolismo , RatasRESUMEN
OBJECTIVES: The objective of this study was to develop and validate a multicenter-based, multi-model, time-series deep learning model for predicting drug-induced liver injury (DILI) in patients taking angiotensin receptor blockers (ARBs). The study leveraged a national-level multicenter approach, utilizing electronic health records (EHRs) from six hospitals in Korea. METHODS: A retrospective cohort analysis was conducted using EHRs from six hospitals in Korea, comprising a total of 10,852 patients whose data were converted to the Common Data Model. The study assessed the incidence rate of DILI among patients taking ARBs and compared it to a control group. Temporal patterns of important variables were analyzed using an interpretable timeseries model. RESULTS: The overall incidence rate of DILI among patients taking ARBs was found to be 1.09%. The incidence rates varied for each specific ARB drug and institution, with valsartan having the highest rate (1.24%) and olmesartan having the lowest rate (0.83%). The DILI prediction models showed varying performance, measured by the average area under the receiver operating characteristic curve, with telmisartan (0.93), losartan (0.92), and irbesartan (0.90) exhibiting higher classification performance. The aggregated attention scores from the models highlighted the importance of variables such as hematocrit, albumin, prothrombin time, and lymphocytes in predicting DILI. CONCLUSIONS: Implementing a multicenter-based timeseries classification model provided evidence that could be valuable to clinicians regarding temporal patterns associated with DILI in ARB users. This information supports informed decisions regarding appropriate drug use and treatment strategies.
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Pharmacovigilance involves monitoring of drugs and their adverse drug reactions (ADRs) and is essential for their safety post-marketing. Because of the different types and structures of medical databases, several previous surveillance studies have analyzed only one database. In the present study, we extracted potential drug-ADR pairs from electronic health record (EHR) data using the MetaNurse algorithm and analyzed them using the Korean Adverse Event Reporting System (KAERS) database for systematic validation. The Medical Dictionary for Regulatory Activities (MedDRA) and World Health Organization (WHO) Adverse Reactions Terminology (WHO-ART) were mapped for signal detection. We used the Side Effect Resource (SIDER) database to select 2663 drug-ADR pairs to investigate unknown drug-induced ADRs. The reporting odds ratio (ROR) value was calculated for the drug-exposed and non-exposed groups of drug-ADR pairs, and 19 potential pairs showed significant signals. Appropriate terminology systems and criteria are needed to handle diverse medical databases.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Registros Electrónicos de Salud , Sistemas de Registro de Reacción Adversa a Medicamentos , Algoritmos , Bases de Datos Factuales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Humanos , República de CoreaRESUMEN
OBJECTIVES: The established Beers Criteria consider side effects and safety concerns when prescribing drugs to the elderly. As the criteria suggest that attention should be paid toward prescriptions rather than prescription prohibition lists, these Beers Criteria medications (BCMs) are used appropriately under unavoidable circumstances. METHODS: Patients aged ≥ 65 years and with an experience of being prescribed inappropriate medications at Konyang University Hospital, South Korea, were selected. We analyzed data from the Korea Adverse Event Reporting System (KAERS) and the Food and Drug Administration Adverse Event Reporting System (FAERS) of the United States to identify medication-induced adverse drug events (ADEs). The actual incidence was predicted by multiplying the incidence and number of BCMs prescribed to the patients. The proportional reporting ratio (PRR) and reporting odds ratio (ROR) were calculated using KAERS and FAERS data. RESULTS: We predicted that the incidence of ADEs would be higher for metoclopramide, chlorpheniramine, and amitriptyline in patients using medications for more than 1 day and metoclopramide, chlorpheniramine, and ketoprofen in patients using medications only for 1 day. Among the ADEs reported to KAERS and FAERS, significant ROR and PRR values were noted for clonazepam (drowsiness), nortriptyline (sleepiness), and zolpidem (amnesia, somnambulism, agitation, dependence, nightmare, and dysgeusia). CONCLUSION: This study highlighted the actual status of BCM prescriptions in clinical institutions and predicted the incidence of ADEs. We concluded that greater care must be taken while prescribing BCMs to the elderly and indicators, such as PRR and ROR should be monitored regularly.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Geriatría , Preparaciones Farmacéuticas , Anciano , Prescripciones de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Humanos , Lista de Medicamentos Potencialmente Inapropiados , Estados Unidos/epidemiologíaRESUMEN
The present study aimed to investigate expression of ß2-adrenergic receptor (AR), the effect of the stress-related neurotransmitter norepinephrine (NE) on cell viability, proliferation and the therapeutic effect of propranolol, which is a typical ß-blocker in various type of head and neck cancers for the first time. The ß2-AR expression was investigated using immunohistochemistry and an immunoreactive scoring (IRS) system in 57 different head and neck cancer specimens, and reverse transcriptase-polymerase chain reaction and western blotting in four head and neck cancer cell lines (HNCCLs). Cell viability and proliferation assays were performed using 0, 1, 5 and 10 µM of NE and 1 µM of propranolol in four HNCCLs. The expression of ß2-AR was positive in the majority of head and neck cancer tissues (55/57, 96.5%); however, it was significantly higher in oral cavity cancer than in pharyngeal cancer (median IRS: 9 vs. 3; P<0.001). All HNCCLs exhibited ß2-AR expression, with a higher expression level detected in the oral cavity cancer cell line than in the others. NE stimulated viability (oral cavity, 206%; larynx, 156%; pharynx, 130%; nasal cavity, 137%; 10 µM NE) and proliferation (124, 176, 131 and 127%, respectively) in a dose-dependent manner in all HNCCLs. Conversely, propranolol attenuated such viability (55, 42, 18 and 22%, respectively) and proliferation (22, 40, 61 and 48%, respectively). In conclusion, the viability and proliferation of various head and neck cancers may be directly stimulated by stress and this may be attenuated by ß-blockers.
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As life spans increased, neurodegenerative disorders that affect aging populations have also increased. Progressive neuronal loss in specific brain regions is the most common cause of neurodegenerative disease; however, key determinants mediating neuron loss are not fully understood. Using a model of mitochondrial membrane potential (ΔΨm) loss, we found only 25% cell loss in SH-SY5Y (SH) neuronal mono-cultures, but interestingly, 85% neuronal loss occurred when neurons were co-cultured with BV2 microglia. SH neurons overexpressing uncoupling protein 2 exhibited an increase in neuron-microglia interactions, which represent an early step in microglial phagocytosis of neurons. This result indicates that ΔΨm loss in SH neurons is an important contributor to recruitment of BV2 microglia. Notably, we show that ΔΨm loss in BV2 microglia plays a crucial role in microglial activation and phagocytosis of damaged SH neurons. Thus, our study demonstrates that ΔΨm loss in both neurons and microglia is a critical determinant of neuron loss. These findings also offer new insights into neuroimmunological and bioenergetical aspects of neurodegenerative disease.