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BACKGROUND: We aimed to examine whether patients with de novo and relapsed/progressed stage IIIB-IV non-small cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations have different prognoses. METHODS: This retrospective study analyzed the Health Insurance Review and Assessment claims data in South Korea from 2013 to 2020. Patients with stage IIIB-IV NSCLC without EGFR or ALK mutations who received first-line palliative therapy between 2015 and 2019 were identified. Overall survival (OS), time to first subsequent therapy (TFST), and time to second subsequent therapy (TSST) were estimated using the Kaplan-Meier method. Multivariate Cox regression analysis was used to reveal the impact of de novo versus relapsed/progressed disease on OS. Treatment patterns, including treatment sequence, top five most frequent regimens, and time to treatment discontinuation, were described in both groups. RESULTS: Of 14,505 patients, 12,811 (88.3%) were de novo, and 1,694 (11.7%) were relapsed/progressed. The median OS in the de novo group was 11.0 versus 11.5 months in the relapsed/progressed group (P = 0.002). The ongoing treatment probability was higher in relapsed/progressed patients than in de novo patients from 6.4 months since the initiation of first-line treatment (P < 0.001). Median TSST was shorter in the de novo group than in the relapsed/progressed group (9.5 vs. 9.9 months, P < 0.001). In multivariate analysis, de novo disease was associated with shorter OS (hazard ratio 1.07; 95% confidence interval 1.01-1.14). The overall treatment patterns for de novo and relapsed/progressed patients were similar. CONCLUSIONS: De novo patients had poorer OS and TSST after the initiation of palliative therapy than relapsed/progressed patients. These findings suggest that the stage of the disease at the time of initial diagnosis should be considered in observational studies and clinical trials as a prognostic factor.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Estudos RetrospectivosRESUMO
Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensing O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in O-GlcNAc signaling in macrophages. O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing O-GlcNAc signaling by O-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.
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Macrófagos/imunologia , N-Acetilglucosaminiltransferases/imunologia , Obesidade/imunologia , Proteínas Quinases S6 Ribossômicas 90-kDa/imunologia , Acetilglucosamina/imunologia , Tecido Adiposo/imunologia , Animais , Humanos , Ativação de Macrófagos , Macrófagos/enzimologia , Camundongos , Camundongos Knockout , N-Acetilglucosaminiltransferases/genética , Obesidade/enzimologia , Obesidade/genética , Obesidade/metabolismo , Fosforilação , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Transdução de SinaisRESUMO
BACKGROUND: Regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB) have been changed from injectable-containing regimens to all-oral regimens. The economic effectiveness of new all-oral regimens compared with conventional injectable-containing regimens was scarcely evaluated. This study was conducted to compare the cost-effectiveness between all-oral longer-course regimens (the oral regimen group) and conventional injectable-containing regimens (the control group) to treat newly diagnosed MDR-TB patients. METHODS: A health economic analysis over lifetime horizon (20 years) from the perspective of the healthcare system in Korea was conducted. We developed a combined simulation model of a decision tree model (initial two years) and two Markov models (remaining 18 years, six-month cycle length) to calculate the incremental cost-effectiveness ratio (ICER) between the two groups. The transition probabilities and cost in each cycle were assumed based on the published data and the analysis of health big data that combined country-level claims data and TB registry in 2013-2018. RESULTS: The oral regimen group was assumed to spend 20,778 USD more and lived 1.093 years or 1.056 quality-adjusted life year (QALY) longer than the control group. The ICER of the base case was calculated to be 19,007 USD/life year gained and 19,674 USD/QALY. The results of sensitivity analyses showed that base case results were very robust and stable, and the oral regimen was cost-effective with a 100% probability for a willingness to pay more than 21,250 USD/QALY. CONCLUSION: This study confirmed that the new all-oral longer regimens for the treatment of MDR-TB were cost-effective in replacing conventional injectable-containing regimens.
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Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Análise Custo-Benefício , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Protocolos Clínicos , República da Coreia , Anos de Vida Ajustados por Qualidade de VidaRESUMO
Liver fibrosis is a common characteristic of chronic liver diseases. The activation of hepatic stellate cells (HSCs) plays a key role in fibrogenesis in response to liver injury, yet the mechanism by which damaged hepatocytes modulate the activation of HSCs is poorly understood. Our previous studies have established that liver-specific deletion of O-GlcNAc transferase (OGT)leads to hepatocyte necroptosis and spontaneous fibrosis. Here, we report that OGT-deficient hepatocytes secrete trefoil factor 2 (TFF2) that activates HSCs and contributes to the fibrogenic process. The expression and secretion of TFF2 are induced in OGT-deficient hepatocytes but not in WT hepatocytes. TFF2 activates the platelet-derived growth factor receptor beta signaling pathway that promotes the proliferation and migration of primary HSCs. TFF2 protein expression is elevated in mice with carbon tetrachloride-induced liver injury. These findings identify TFF2 as a novel factor that mediates intercellular signaling between hepatocytes and HSCs and suggest a role of the hepatic OGT-TFF2 axis in the process of fibrogenesis.
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Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Cirrose Hepática/metabolismo , Fator Trefoil-2/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Linhagem Celular , Células Cultivadas , Exocitose , Células Estreladas do Fígado/patologia , Hepatócitos/patologia , Humanos , Cirrose Hepática/etiologia , Camundongos , N-Acetilglucosaminiltransferases/deficiência , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Necroptose , Transdução de Sinais , Fator Trefoil-2/genéticaRESUMO
BACKGROUND: In systems biology, it is of great interest to identify previously unreported associations between genes. Recently, biomedical literature has been considered as a valuable resource for this purpose. While classical clustering algorithms have popularly been used to investigate associations among genes, they are not tuned for the literature mining data and are also based on strong assumptions, which are often violated in this type of data. For example, these approaches often assume homogeneity and independence among observations. However, these assumptions are often violated due to both redundancies in functional descriptions and biological functions shared among genes. Latent block models can be alternatives in this case but they also often show suboptimal performances, especially when signals are weak. In addition, they do not allow to utilize valuable prior biological knowledge, such as those available in existing databases. RESULTS: In order to address these limitations, here we propose PALMER, a constrained latent block model that allows to identify indirect relationships among genes based on the biomedical literature mining data. By automatically associating relevant Gene Ontology terms, PALMER facilitates biological interpretation of novel findings without laborious downstream analyses. PALMER also allows researchers to utilize prior biological knowledge about known gene-pathway relationships to guide identification of gene-gene associations. We evaluated PALMER with simulation studies and applications to studies of pathway-modulating genes relevant to cancer signaling pathways, while utilizing biological pathway annotations available in the KEGG database as prior knowledge. CONCLUSIONS: We showed that PALMER outperforms traditional latent block models and it provides reliable identification of novel gene-gene associations by utilizing prior biological knowledge, especially when signals are weak in the biomedical literature mining dataset. We believe that PALMER and its relevant user-friendly software will be powerful tools that can be used to improve existing pathway annotations and identify novel pathway-modulating genes.
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Algoritmos , Mineração de Dados , Modelos Teóricos , Anotação de Sequência Molecular , Publicações , Simulação por Computador , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Família Multigênica , Biologia de SistemasRESUMO
There are two key challenges when using a linear discriminant analysis in the high-dimensional setting, including singularity of the covariance matrix and difficulty of interpreting the resulting classifier. Although several methods have been proposed to address these problems, they focused only on identifying a parsimonious set of variables maximizing classification accuracy. However, most methods did not consider dependency between variables and efficacy of selected variables appropriately. To address these limitations, here we propose a new approach that directly estimates the sparse discriminant vector without a need of estimating the whole inverse covariance matrix, by formulating a quadratic optimization problem. Furthermore, this approach also allows to integrate external information to guide the structure of covariance matrix. We evaluated the proposed model with simulation studies. We then applied it to the transcriptomic study that aims to identify genomic markers predictive of the response to cancer immunotherapy, where the covariance matrix was constructed based on the prior knowledge available in the pathway database.
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Visualization algorithms have been widely used for intuitive interrogation of genomic data and popularly used tools include MDS, t-SNE, and UMAP. However, these algorithms are not tuned for the visualization of binary data and none of them consider the hubness of observations for the visualization. In order to address these limitations, here we propose hubViz, a novel tool for hub-centric visualization of binary data. We evaluated the performance of hubViz with its application to the gene expression data measured in multiple brain regions of rats exposed to cocaine, the single-cell RNA-seq data of peripheral blood mononuclear cells treated with interferon beta, and the literature mining data to investigate relationships among diseases. We further evaluated the performance of hubViz using simulation studies. We showed that hubViz provides effective visual inspection by locating the hub in the center and the contrasting elements in the opposite sides around the center. We believe that hubViz and its software can be powerful tools that can improve visualizations of various genomic data. The hubViz is implemented as an R package hubviz, which is publicly available at https://dongjunchung.github.io/hubviz/.
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OBJECTIVES: We investigated the risk of dementia associated with the use of proton pump inhibitors (PPIs) as compared with the use of histamine-2 receptor antagonist (H2RA). METHODS: We conducted retrospective propensity score-matched cohort study using the National Health Insurance Service-National Sample Cohort. Subjects were defined as the patients newly prescribed with PPI or H2RA between 2003 and 2013 without prior prescriptions of PPI/H2RA or diagnosis of dementia from their history within the past 1 year. We followed up participants until dementia occurrence, death, or the end of the study, whichever occurred first, with an intention-to-treat approach. A 1-year lag time between exposure and outcome measure was used to reduce protopathic bias. The incidence rate per 1000 person-years was estimated. The incidence rate of PPI was compared with that of H2RA, defined as incidence rate ratio (IRR), calculated with a 95% confidence interval. To control for potential confounds, propensity score matching at a 1:1 ratio was conducted, and the crude IRR was adjusted by risk factors. RESULTS: Our propensity score-matched cohort included 87 562 patients on PPIs and 87 562 patients on H2RAs. The IRR was 1.01 (95% confidence interval 0.96-1.06) with 1-year lag time. IRR showed the decreased trend as the longer lag time. Also, no treatment duration or dose-response relationship was observed. CONCLUSIONS: Our finding demonstrated that PPIs did not associate with dementia more strongly than did H2RA. On this basis, we suggest that the previously reported risk for dementia associated with PPI may have been overestimated.
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Demência/induzido quimicamente , Inibidores da Bomba de Prótons/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Demência/epidemiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Inibidores da Bomba de Prótons/administração & dosagem , República da Coreia/epidemiologia , Estudos Retrospectivos , Medição de Risco/métodos , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Osteoarthritis is highly prevalent in older adults and often treated with nonsteroidal anti-inflammatory drugs (NSAIDs). COX-2-selective NSAIDs have been shown to offer better gastrointestinal (GI) safety benefits than non-selective NSAIDs (ns-NSAIDs). However, most COX-2-selective NSAIDs have not been comprehensively evaluated for use in combination with gastroprotective agents (GPAs). This study compared the risk of adverse GI events in patients treated with COX-2-selective NSAIDs and ns-NSAIDs alone, or in combination with GPAs. MATERIALS AND METHODS: We utilized National Health Insurance Claim Data collected from 2012 to 2015. Newly diagnosed patients with osteoarthritis (60 years or older) were included in this study. The study population was divided into two groups: 1) COX-2-selective NSAID treatment and 2) ns-NSAIDs treatment. Patients were followed-up for up to 6 months to determine whether GI events occurred. The Cox proportional hazards model was used to identify differences in risk. Subgroup analyses were conducted for monotherapies and combination treatments with GPAs. RESULTS: The number of subjects prescribed COX-2-selective NSAID and ns-NSAIDs were 20,868 (5.6%) and 353,494 (94.4%), respectively. After adjustment for confounding factors, COX-2-selective NSAID were safer than ns-NSAIDs (adjusted hazard ratio (aHR) = 0.80, 95% confidence interval (CI): 0.77 - 0.82). Use of GPAs with COX-2-selective NSAID was associated with a lower risk of GI events than use of ns-NSAIDs (aHR = 0.92, 95% CI: 0.87 - 0.97). CONCLUSION: Use of COX-2-selective NSAID was associated with a lower risk of GI adverse events than use of ns-NSAIDs as a monotherapy. Furthermore, COX-2-selective NSAID were safer than ns-NSAIDs in combination with GPAs.â©.
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Anti-Inflamatórios não Esteroides/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Gastroenteropatias/induzido quimicamente , Osteoartrite/tratamento farmacológico , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Humanos , Estudos RetrospectivosRESUMO
PURPOSE: To evaluate whether the concurrent use of benzodiazepines, antidepressants, and opioid analgesics with zolpidem increases the risk of suicide or triggers suicide compared with the use of zolpidem alone. METHODS: We conducted a case-control and case-crossover study using the Korean National Health Insurance Service-National Sample Cohort database. Cases were older than 20 years with a suicide record (International Codes of Disease 10th Revision codes: X-60-X84 and Y87.0 intentional self-harm) between January 1, 2004, and December 31, 2013. For case-control design, ten controls were matched to each case by age, sex, index year, region, income, and health insurance type. For case-crossover analysis, we set hazard period to 60 days and assigned five corresponding sets of control periods of equal length. Exposure was assessed during 60 days before suicide for combinations of benzodiazepines, antidepressants, opioid analgesics with zolpidem against zolpidem alone. We conducted a conditional logistic regression to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: In the case-control study, the risk of suicide was 2.80-fold higher in cases taking benzodiazepines and antidepressants with zolpidem than in those taking zolpidem alone (adjusted OR [aOR], 2.80; 95% CI, 1.38-5.70). However, in the case-crossover study, suicide risk showed no significant difference (crude OR [cOR], 0.92; 95% CI, 0.55-1.52) and was underpowered. CONCLUSIONS: The results of the traditional case-control study confirmed that the concurrent use of benzodiazepines and antidepressants with zolpidem was associated with an increased risk of suicide compared with the use of zolpidem alone. However, there was no significant difference in the magnitude of risk in the within-person comparison design.
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Analgésicos Opioides/administração & dosagem , Antidepressivos/administração & dosagem , Benzodiazepinas/administração & dosagem , Comportamento Autodestrutivo/induzido quimicamente , Suicídio/estatística & dados numéricos , Zolpidem/administração & dosagem , Adulto , Idoso , Estudos de Casos e Controles , Estudos Cross-Over , Bases de Dados Factuais , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de RiscoRESUMO
BACKGROUND: Poor adherence to tuberculosis (TB) treatment is an obstacle to controlling the disease. The Korean government's national TB control plan includes a program on adherence to TB treatment to manage patients with TB. This study aimed to assess the cost-effectiveness of a national TB program for improving patient adherence. METHODS: A discrete event simulation (DES) model was developed to estimate the costs and quality-adjusted life-years (QALYs) of adherent and non-adherent patients. In this model, we considered treatment completion, loss to follow-up, recurrence, death, and treatment changes from drug-susceptible to multidrug-resistant TB as clinical events. We obtained input parameters such as costs, probability of events, and time distributions for each event from the Korean National Health Insurance claims data. We estimated the costs and QALYs before implementation of the program (adherence rate = 79%) and at present (current adherence rate = 94%). The incremental cost-effectiveness ratio (ICER) was used to evaluate whether the program was cost-effective given the willingness-to-pay threshold. RESULTS: In the simulation, the program increasing the proportion of adherent patients gained 0.018 QALY/patient while spending $162/patient. The ICER of the TB program was $8790/QALY. Given a willingness-to-pay threshold of $20,000, the national TB program was considered cost-effective. CONCLUSION: Improvements in adherence to TB treatment through the current TB program were cost-effective. The DES model accurately reflected the real world. Commitment programs to improve patient adherence may help manage TB nationwide.
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Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Análise Custo-Benefício , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Cooperação do Paciente , República da Coreia , Anos de Vida Ajustados por Qualidade de VidaRESUMO
PURPOSE: There is a lack of real-world data in Asian populations for brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor for patients with non-small cell lung cancer (NSCLC). This study analysed real-world outcomes and dosing patterns for brigatinib in patients with crizotinib-refractory ALK+ NSCLC in South Korea. METHODS: This retrospective, non-interventional, cohort study used South Korean Health Insurance and Review Assessment claims data for adults with ALK+ NSCLC who initiated brigatinib between 19 April 2019 and 31 March 2021 after receiving prior crizotinib. Patients' characteristics, time to discontinuation (TTD), time to dose reduction, overall survival (OS) and treatment adherence were assessed. RESULTS: The study included 174 patients (56.9% male; 27.0% with a history of brain metastases). Median duration of prior crizotinib was 17 (range 0.3-48) months. Median follow-up after brigatinib initiation was 18 (range 0-34) months. Overall, 88.5% of patients received full-dose brigatinib (180 mg/day) and 93.1% of patients were adherent (proportion of days covered ≥0.8). The median TTD was 24.9 months (95% CI 15.2-not reached). The probability of continuing treatment was 63.2% at 1 year and 51.5% at 2 years. The probability of continuing at full or peak dose was 79.7% at 1 year and 75.6% at 2 years. Median OS was not reached. The 2-year OS rate was 68.7%. CONCLUSIONS: In this first nationwide retrospective study using national insurance claim data, brigatinib demonstrated real-world clinical benefit as second-line treatment after prior crizotinib in ALK+ NSCLC patients in South Korea.
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Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas , Crizotinibe , Neoplasias Pulmonares , Compostos Organofosforados , Pirimidinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Masculino , Feminino , República da Coreia , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Estudos Retrospectivos , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Adulto , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Idoso , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: We assessed the real-world effectiveness of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors as first-line treatments in postmenopausal patients with HR+/HER2- advanced breast cancer, focusing on younger (<45 years) and older (>78 years) populations not considered in clinical trials. METHODS: We analyzed nationwide claims data from the Health Insurance Review and Assessment Service between November 2016 and February 2021. In this retrospective cohort study, patients using CDK4/6 inhibitors and aromatase inhibitors were selected and grouped by age as follows: 45-78 years (trial-enrolled), <45 years (younger), and >78 years (older). We estimated the median real-world progression-free survival (rwPFS) and overall survival (OS) using the Kaplan-Meier method. We conducted Cox regression analysis using a sub-distribution hazard model to evaluate risk factors (age, history of prior systemic treatment, presence of metastasis, comorbidity index, and type of provider) and estimated hazard ratios (HR). RESULTS: Among the 2,830 patients who received CDK4/6 inhibitors as first-line therapy, we identified 358 (12.65%) younger and 148 (5.23%) older underrepresented patients. The younger patient group (50.84%) had the highest rate of prior systemic therapy, followed by the trial-enrolled (25.39%) and older patient groups (8.11%). The median rwPFS was shorter in the older group (19.30 months) than those in the younger and the trial-enrolled age groups (30.33 and 34.53 months, respectively; p = .002). The HR of older age for death was 1.59 (95% confidence interval (CI) = 1.24-2.03). For rwPFS, the HR of prior systemic therapy was 1.19 (95% CI = 1.04-1.37). CONCLUSIONS: The younger age group, which was underrepresented in the trial, did not show a significant difference in risk compared with the enrolled age group. However, the older age group, which was also underrepresented in the trial, faces a risk of mortality but not progression. Patients who fall outside the specified age groups for the clinical trial can still expect the same level of effectiveness in terms of progression.
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OBJECTIVE: This study was conducted to investigate the effects of glucagon-like peptide-1 receptor (GLP-1) agonists on the lipid profiles of patients with type 2 diabetes. METHODS: We retrieved the data of phase 3 randomized controlled trials on GLP-1 agonists in patients with type 2 diabetes from the PubMed, Embase, and Cochrane library up to 11 February 2024. We extracted % changes in low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol/total cholesterol (T-CHO) and triglycerides levels from baseline. Using Bayesian network meta-analysis, mean differences and 95% credible intervals for lipid changes were estimated as a unit of percentage points (%p) by class. RESULTS: Twenty-six studies covering 22,290 participants were included. The glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 dual agonist showed significant differences in LDL-C (range of mean differences: -11.61 to -6.77%p), triglycerides (-19.94 to -13.31%p), and T-CHO (-7.94 to -5.09%p) levels compared to placebo, insulin, and sodium-glucose co-transporter 2 (SGLT2) inhibitors. The GLP-1 agonist significantly reduced T-CHO (-5.20%p; -6.39%p) and LDL-C (-4.32%p; -8.17%p) levels compared to placebo and SGLT2 inhibitors, respectively. CONCLUSIONS: The GIP/GLP-1 dual agonist positively affects the lipid profiles of patients with type 2 diabetes. This may contribute to a lower risk of cardiovascular disease in patients with type 2 diabetes. PROTOCOL REGISTRATION: PROSPERO (CRD42021282668).
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Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Lipídeos , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Humanos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/farmacologia , Hipoglicemiantes/administração & dosagem , Lipídeos/sangue , Triglicerídeos/sangue , LDL-Colesterol/sangue , Teorema de Bayes , Agonistas do Receptor do Peptídeo 1 Semelhante ao GlucagonRESUMO
Importance: Proton pump inhibitors (PPIs) are commonly used drugs to relieve gastrointestinal tract symptoms, but their acid-inhibitory action negatively affects the bioavailability and clinical outcomes of orally administered concomitant drugs. Objective: To identify the clinical outcomes of patients with advanced breast cancer who concomitantly use PPIs and palbociclib. Design, Setting, and Participants: This retrospective cohort study used nationwide claims data between November 1, 2016, and July 31, 2021, in South Korea. Patients with breast cancer receiving palbociclib between November 1, 2017, and July 31, 2020, were identified. Patients whose prescriptions for palbociclib and PPI overlapped by at least 33% were classified into a concomitant PPI group. Patients who never received PPI during the palbociclib treatment period were classified into a nonconcomitant PPI group. Patients were selected through 1:3 propensity score matching for analyses. Exposures: Concomitant use of PPIs with palbociclib. Main Outcomes and Measures: Time to progression and death. These outcomes were presented as progression-free survival (PFS) and overall survival (OS) and were analyzed using the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was used to estimate the hazard ratio (HR) of concomitant PPI use associated with clinical PFS and/or OS. Results: A total of 344 women were included in the concomitant PPI group and 966 in the nonconcomitant PPI group. Among 1310 patients identified after matching, 1108 (84.6%) were older than 50 years; 1111 (84.8%) were treated with letrozole and anastrozole (endocrine sensitive); and 199 (15.2%) were treated with fulvestrant (endocrine resistant). The median clinical PFS in the concomitant PPI group was shorter than that of the nonconcomitant PPI group (25.3 [95% CI, 19.6-33.0] vs 39.8 [95% CI, 34.9 to not applicable] months; P < .001), and the HR was 1.76 (95% CI, 1.46-2.13). Concomitant use of PPI was also associated with shorter OS (HR, 2.71 [95% CI, 2.07-3.53]). Both clinical PFS and OS in the concomitant PPI group were consistently poor in patients receiving endocrine-sensitive and endocrine-resistant treatment. Conclusions and Relevance: These findings suggest that concomitant use of PPIs with palbociclib may hinder the complete therapeutic benefits of palbociclib in patients with breast cancer.
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Neoplasias da Mama , Humanos , Feminino , Inibidores da Bomba de Prótons/uso terapêutico , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Genome-wide association studies (GWAS) have successfully identified a large number of genetic variants associated with traits and diseases. However, it still remains challenging to fully understand the functional mechanisms underlying many associated variants. This is especially the case when we are interested in variants shared across multiple phenotypes. To address this challenge, we propose graph-GPA 2.0 (GGPA 2.0), a statistical framework to integrate GWAS datasets for multiple phenotypes and incorporate functional annotations within a unified framework. Our simulation studies showed that incorporating functional annotation data using GGPA 2.0 not only improves the detection of disease-associated variants, but also provides a more accurate estimation of relationships among diseases. Next, we analyzed five autoimmune diseases and five psychiatric disorders with the functional annotations derived from GenoSkyline and GenoSkyline-Plus, along with the prior disease graph generated by biomedical literature mining. For autoimmune diseases, GGPA 2.0 identified enrichment for blood-related epigenetic marks, especially B cells and regulatory T cells, across multiple diseases. Psychiatric disorders were enriched for brain-related epigenetic marks, especially the prefrontal cortex and the inferior temporal lobe for bipolar disorder and schizophrenia, respectively. In addition, the pleiotropy between bipolar disorder and schizophrenia was also detected. Finally, we found that GGPA 2.0 is robust to the use of irrelevant and/or incorrect functional annotations. These results demonstrate that GGPA 2.0 can be a powerful tool to identify genetic variants associated with each phenotype or those shared across multiple phenotypes, while also promoting an understanding of functional mechanisms underlying the associated variants.
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Finding safe solvents with low viscosities has been in great demand in extraction processes. Herein, R-(-)-carvone, a natural monoterpenoid rich in spearmint, was mixed with naturally occurring fatty acids and terpenes. Most eutectic mixtures presented a wide liquid window in the solid-liquid equilibrium phase diagrams. Carvone mixtures at the ideal eutectic points were characterized for physicochemical properties. Despite varying properties, all the tested solvents were immiscible with water and displayed low viscosity with reasonable biodegradability. Sigma potentials of the mixtures were applied to machine learning algorithms, suggesting carvone mixtures as substitutes for polar protic and dipolar aprotic solvents. Carvone mixtures could be successfully applied to liquid-liquid extraction of a red algae called laver, which is rich in natural hydrophobic and hydrophilic pigments of high value. This study proposes carvone as a new bio-based source of hydrophobic solvents and the eutectic mixtures as biodegradable and tunable solvents to extract hydrophobic compounds.
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Água , Monoterpenos Cicloexânicos , Interações Hidrofóbicas e Hidrofílicas , SolventesRESUMO
Objectives: We analyzed tuberculosis (TB)-related costs according to treatment adherence, as well as the association between treatment adherence, treatment outcomes, and costs related to drug-susceptible TB in South Korea. Methods: Patients who had newly treated TB in South Korea between 2006 and 2015 were selected from nationwide sample claims data and categorized into adherent and non-adherent groups using the proportion of days TB drugs covered. Patients were followed-up from the initiation of TB treatment. The mean five-year cumulative costs per patient were estimated according to adherence. Moreover, we evaluated the relative ratios to identify cost drivers such as adherence, treatment outcomes, and baseline characteristics using generalized linear models. Four treatment outcomes were included: treatment completion, loss to follow-up, death, and the initiation of multidrug-resistant TB treatment. Results: Out of the 3,799 new patients with TB, 2,662 were adherent, and 1,137 were non-adherent. Five years after initiating TB treatment, the mean TB-related costs were USD 2,270 and USD 2,694 in the adherent and non-adherent groups, respectively. The TB-related monthly cost per patient was also lower in the adherent than in the non-adherent (relative ratio = 0.89, 95% CI 0.92-0.98), while patients who were lost to follow-up spent more on TB-related costs (2.52, 2.24-2.83) compared to those who completed the treatment. Conclusion: Non-adherent patients with TB spend more on treatment costs while they have poorer outcomes compared to adherent patients with TB. Improving patient adherence may lead to effective treatment outcomes and reduce the economic burden of TB. Policymakers and providers should consider commitment programs to improve patient's adherence.
RESUMO
BACKGROUND: Despite valsartan's widespread use, few studies have explored its potential carcinogenicity. We evaluated the association between valsartan and cancer. METHODS: We conducted a retrospective cohort study using data from 2002 to 2015 gathered from the National Health Insurance database. Patients with hypertension aged ≥ 30 who used valsartan or other angiotensin II receptor blockers (ARBs) were included. Eligible patients were those with no prior history of the use of any ARBs, diagnosis of cancer, or organ transplantation in the 4 years predating their first use of the drugs of interest. The primary and secondary outcomes included the occurrence of all cancers and site-specific solid cancers, respectively. After applying propensity score (PS) matching, Cox regression was used to calculate the hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS: A total of 1,550,734 individuals were identified as new users of valsartan or other ARBs. Of the 153,047 valsartan users, 16,047 were diagnosed with cancer. No increased risk of overall cancer was observed in valsartan users as compared to other ARB users (aHR = 1.00; 95 % CI, 0.98-1.02). Valsartan was, however, associated with a slightly elevated risk of liver (aHR = 1.09; 95 % CI, 1.01-1.16) and kidney cancer (aHR = 1.11; 95 % CI, 1.02-1.22). CONCLUSION: Compared with other ARBs, valsartan did not increase the risk of overall cancer. A slightly increased risk for some solid cancers was associated with valsartan use, though the absolute rate difference was small.
Assuntos
Antagonistas de Receptores de Angiotensina , Neoplasias , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Estudos de Coortes , Humanos , Neoplasias/induzido quimicamente , Neoplasias/epidemiologia , Estudos Retrospectivos , Valsartana/efeitos adversosRESUMO
Background: The utility values are increasingly being used in economic evaluations and health policy decision making. This study aims to conduct a systematic literature review and meta-analysis of the utility values for asthma, particularly with respect to severity and asthma control. Materials and methods: A literature search was conducted using the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases for studies published until July, 2020, reporting the utilities of adult asthma. We extracted utility values derived by nine indirect and four direct utility instruments. Meta-analyses were performed for each utility instrument according to health states based on the level of asthma control and severity. Results: Fifty-two eligible studies were included in our systematic review, of which forty studies were used in the meta-analyses. Among the 13 utility instruments, the most used was EQ-5D-3L, whereas EQ-5D-5L showed the narrowest 95% confidence interval (95% CI, 0.83-0.86) of pooled utility. The pooled utility of asthma declined with worsening control levels and severity. The pooled utility value of EQ-5D-3L was 0.72 (95% CI, 0.63-0.80) for uncontrolled, 0.82 (95% CI, 0.75-0.88) for partly controlled, and 0.87 (95% CI, 0.84-0.90) for well-controlled asthma. Conclusion: Our study shows that EQ-5D-3L and EQ-5D-5L are appropriate for economic evaluations in terms of availability and variability of information, respectively. Asthma patients had poorer utility values with worsened severity and level of asthma control. This study will be useful for health economists conducting economic evaluations of asthma treatments.