Real-world evidence of brigatinib as second-line treatment after crizotinib for ALK+ non-small cell lung cancer using South Korean claims data (K-AREAL).

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.

Lipid profile changes induced by glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a systematic review and network meta-analysis.

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).

Real-world effectiveness of CDK4/6 inhibitors on patients with HR+/HER2- advanced breast cancer in South Korea, focusing on underrepresented patients.

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.

Concomitant Use of Proton Pump Inhibitors and Palbociclib Among Patients With Breast Cancer.

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.

Survival differences between patients with de novo and relapsed/progressed advanced non-small cell lung cancer without epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements.

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.

Visual Outcomes and Optical Quality of Accommodative, Multifocal, Extended Depth-of-Focus, and Monofocal Intraocular Lenses in Presbyopia-Correcting Cataract Surgery: A Systematic Review and Bayesian Network Meta-analysis.

Importance: A bayesian network meta-analysis (NMA) can help compare the various types of multifocal and monofocal intraocular lenses (IOLs) used in clinical practice. Objective: To compare outcomes of presbyopia-correcting IOLs frequently recommended in clinical practice through a bayesian NMA based on a systematic review. Data Sources: Medline (PubMed) and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched on May 15, 2021, from inception. Study Selection: Based on the research question, randomized clinical trials assessing multifocal IOLs in patients who underwent bilateral cataract extraction were searched. Nonrandomized studies, studies in patients with unilateral or contralateral cataract extractions, duplicated studies, conference abstracts, and nonpeer-reviewed articles were excluded. Data Extraction and Synthesis: Descriptive statistics and outcomes were extracted. The NMA was conducted to compare different types of IOLs. The mean differences for continuous variables, odds ratios for binary variables, 95% credible intervals (CrIs), and ranks of interventions were estimated. Main Outcomes and Measures: The outcomes examined included binocular visual acuities by distance and optical quality, including glare, halos, and spectacle independence. Results: This NMA included 27 studies comprising 2605 patients. For uncorrected near visual acuity, trifocal IOLs (mean difference, -0.32 [95% CrI, -0.46 to -0.19]) and old bifocal diffractive IOLs (mean difference, -0.33 [95% CrI, -0.50 to -0.14]) afforded better visual acuity than monofocal IOLs. Regarding uncorrected intermediate visual acuity, extended depth-of-focus IOLs provided better visual acuity than monofocal IOLs. However, there were no differences between extended depth-of-focus and trifocal diffractive IOLs in pairwise comparisons. For uncorrected distant visual acuity, all multifocal IOLs were comparable with monofocal IOLs. There were no statistical differences between multifocal and monofocal IOLs regarding contrast sensitivity, glare, or halos. Conclusions and Relevance: For patients considering a multifocal IOL due to presbyopia, bilateral implantation of a trifocal IOL might be an optimal option for patients without compromising distant visual acuity.

Cancer risk associated with the use of valsartan in Korea: A nationwide cohort study.

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.

Clinical manifestation, economic burden, and mortality in patients with transthyretin cardiac amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis, also known as transthyretin cardiomyopathy (ATTR-CM) is a poorly-recognized disease with delayed diagnosis and poor prognosis. This nationwide population-based study aimed to identify disease manifestations, economic burden, and mortality of patients with ATTR-CM. METHODS: Data of newly diagnosed patients with ATTR-CM between 2013 and 2018 from the Korean National Health Insurance Service were used, covering the entire population. Patient characteristics included comorbidities, medical procedures, and medication. Healthcare resource utilization and medical costs were observed as measures of the economic burden. The Kaplan-Meier survival curve and years of potential life lost (YPLL) from the general population were estimated for disease burden with ATTR CM. RESULTS: A total of 175 newly diagnosed patients with ATTR-CM were identified. The most common cardiac manifestation was hypertension (51.3%), while the most common non-cardiac manifestation was musculoskeletal disease (68.0%). Mean medical costs at the post-cohort entry date were significantly higher than those at the pre-cohort entry date ($1,864 vs. $400 per patient per month (PPPM), p < 0.001). Of the total medical costs during the study period, the proportion of inpatients cost was 12.9 times higher than the outpatients cost ($1,730 and $134 PPPM, respectively). The median survival time was 3.53 years from the first diagnosis of ATTR-CM, and the mean (SD) YPLL was 13.0 (7.7). CONCLUSIONS: Patients with ATTR-CM had short survival and high medical costs. To reduce the clinical and economic burdens, carefully examining manifestations of disease in patients can help with early diagnosis and treatment.

Optimal Indicator of Death for Using Real-World Cancer Patients' Data From the Healthcare System.

Background: Information on patient's death is a major outcome of health-related research, but it is not always available in claim-based databases. Herein, we suggested the operational definition of death as an optimal indicator of real death and aim to examine its validity and application in patients with cancer. Materials and methods: Data of newly diagnosed patients with cancer between 2006 and 2015 from the Korean National Health Insurance Service-National Sample Cohort data were used. Death indicators were operationally defined as follows: 1) in-hospital death (the result of treatment or disease diagnosis code from claims data), or 2) case wherein there are no claims within 365 days of the last claim. We estimated true-positive rates (TPR) and false-positive rates (FPR) for real death and operational definition of death in patients with high-, middle-, and low-mortality cancers. Kaplan-Meier survival curves and log-rank tests were conducted to determine whether real death and operational definition of death rates were consistent. Results: A total of 40,970 patients with cancer were recruited for this study. Among them, 12,604 patients were officially reported as dead. These patients were stratified into high- (lung, liver, and pancreatic), middle- (stomach, skin, and kidney), and low- (thyroid) mortality groups consisting of 6,626 (death: 4,287), 7,282 (1,858), and 6,316 (93) patients, respectively. The TPR was 97.08% and the FPR was 0.98% in the high mortality group. In the case of the middle and low mortality groups, the TPR (FPR) was 95.86% (1.77%) and 97.85% (0.58%), respectively. The overall TPR and FPR were 96.68 and 1.27%. There was no significant difference between the real and operational definition of death in the log-rank test for all types of cancers except for thyroid cancer. Conclusion: Defining deaths operationally using in-hospital death data and periods after the last claim is a robust alternative to identifying mortality in patients with cancer. This optimal indicator of death will promote research using claim-based data lacking death information.

PALMER: improving pathway annotation based on the biomedical literature mining with a constrained latent block model.

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.

Sparse Linear Discriminant Analysis using the Prior-Knowledge-Guided Block Covariance Matrix.

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.

OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance.

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.

RNA binding protein PCBP1 is an intracellular immune checkpoint for shaping T cell responses in cancer immunity.

Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Here, we identify the RNA binding protein, poly(C)-binding protein 1 (PCBP1) as an intracellular immune checkpoint that is up-regulated in activated T cells to prevent conversion of effector T (Teff) cells into regulatory T (Treg) cells, by restricting the expression of Teff cell-intrinsic Treg commitment programs. This was critical for stabilizing Teff cell functions and subverting immune-suppressive signals. T cell-specific deletion of Pcbp1 favored Treg cell differentiation, enlisted multiple inhibitory immune checkpoint molecules including PD-1, TIGIT, and VISTA on tumor-infiltrating lymphocytes, and blunted antitumor immunity. Our results demonstrate a critical role for PCBP1 as an intracellular immune checkpoint for maintaining Teff cell functions in cancer immunity.

Real-world treatment persistence of non-tumor necrosis factor inhibitors versus tumor necrosis factor inhibitors among patients with rheumatoid arthritis in South Korea.

Aims: We aimed to assess treatment persistence of tumor necrosis factor (TNF) inhibitors and non-TNF inhibitors in two groups of rheumatoid arthritis (RA) patients: biologic disease-modifying antirheumatic drug (bDMARD) initiators and switchers.Patients and methods: This retrospective cohort study utilized a national health insurance claims database. Patients aged ≥18 years initiating/switching bDMARD between 1 December 2013 and 31 December 2014, the index period, were followed for 12 months. Initiators who began treatment with a bDMARD during the index period were defined as having no bDMARD prescriptions for the previous year. Switchers who changed treatment from the previous bDMARD to the index bDMARD were defined as having different bDMARDs during the index period. Treatment persistence rates during the follow-up period were measured, and factors associated with non-persistence were assessed with the Cox proportional hazard model.Results: Of 2684 patients, treatment persistence rates were the highest for abatacept in initiators (69.3%) and tocilizumab in switchers (77.0%), while adalimumab showed the lowest persistence rates for both initiators and switchers (48.2%, 28.8%), followed by etanercept (51.3%, 41.0%). Adalimumab and etanercept were significantly more likely to show non-persistence (HR 1.58, 95% CI 1.27-1.96; HR 1.42, 95% CI 1.14-1.76) compared to infliximab for initiators, while tocilizumab was significantly more likely to show persistence (HR 0.411, 95% CI 0.206-0.819) in switchers.Conclusions: Non-TNF inhibitors showed higher persistence rates than TNF inhibitors in South Korean RA patients, and tocilizumab especially was associated with higher persistence in patients with inadequate response to TNF inhibitors. Good persistence with non-TNF inhibitors indicates the potential for long-term efficacy as first-line treatment.

O-GlcNAc transferase suppresses necroptosis and liver fibrosis.

Worldwide, over a billion people suffer from chronic liver diseases, which often lead to fibrosis and then cirrhosis. Treatments for fibrosis remain experimental, in part because no unifying mechanism has been identified that initiates liver fibrosis. Necroptosis has been implicated in multiple liver diseases. Here, we report that O-linked ß-N-acetylglucosamine (O-GlcNAc) modification protects against hepatocyte necroptosis and initiation of liver fibrosis. Decreased O-GlcNAc levels were seen in patients with alcoholic liver cirrhosis and in mice with ethanol-induced liver injury. Liver-specific O-GlcNAc transferase-KO (OGT-LKO) mice exhibited hepatomegaly and ballooning degeneration at an early age and progressed to liver fibrosis and portal inflammation by 10 weeks of age. OGT-deficient hepatocytes underwent excessive necroptosis and exhibited elevated protein expression levels of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), which are key mediators of necroptosis. Furthermore, glycosylation of RIPK3 by OGT is associated with reduced RIPK3 protein stability. Taken together, these findings identify OGT as a key suppressor of hepatocyte necroptosis, and OGT-LKO mice may serve as an effective spontaneous genetic model of liver fibrosis.

GAIL: An interactive webserver for inference and dynamic visualization of gene-gene associations based on gene ontology guided mining of biomedical literature.

In systems biology, inference of functional associations among genes is compelling because the construction of functional association networks facilitates biomarker discovery. Specifically, such gene associations in human can help identify putative biomarkers that can be used as diagnostic tools in treating patients. Although biomedical literature is considered a valuable data source for this task, currently only a limited number of webservers are available for mining gene-gene associations from the vast amount of biomedical literature using text mining techniques. Moreover, these webservers often have limited coverage of biomedical literature and also lack efficient and user-friendly tools to interpret and visualize mined relationships among genes. To address these limitations, we developed GAIL (Gene-gene Association Inference based on biomedical Literature), an interactive webserver that infers human gene-gene associations from Gene Ontology (GO) guided biomedical literature mining and provides dynamic visualization of the resulting association networks and various gene set enrichment analysis tools. We evaluate the utility and performance of GAIL with applications to gene signatures associated with systemic lupus erythematosus and breast cancer. Results show that GAIL allows effective interrogation and visualization of gene-gene networks and their subnetworks, which facilitates biological understanding of gene-gene associations. GAIL is available at http://chunglab.io/GAIL/.

Predicting clinical outcome with phenotypic clusters using quantitative CT fibrosis and emphysema features in patients with idiopathic pulmonary fibrosis.

BACKGROUND: The clinical course of IPF varies. This study sought to identify phenotyping with quantitative computed tomography (CT) fibrosis and emphysema features using a cluster analysis and to assess prognostic impact among identified clusters in patient with idiopathic pulmonary fibrosis (IPF). Furthermore, we evaluated the impact of fibrosis and emphysema on lung function with development of a descriptive formula. METHODS: This retrospective study included 205 patients with IPF. A texture-based automated system was used to quantify areas of normal, emphysema, ground-glass opacity, reticulation, consolidation, and honeycombing. Emphysema index was obtained by calculating the percentage of low attenuation area lower than -950HU. We used quantitative CT features and clinical features for clusters and assessed the association with prognosis. A formula was derived using fibrotic score and emphysema index on quantitative CT. RESULTS: Three clusters were identified in IPF patients using a quantitative CT score and clinical values. Prognosis was better in cluster1, with a low extent of fibrosis and emphysema with high forced vital capacity (FVC) than cluster2 and cluster3 with higher fibrotic score and emphysema (p = 0.046, and p = 0.026). In the developed formula [1.5670-fibrotic score(%)*0.04737-emphysema index*0.00304], a score greater ≥ 0 indicates coexisting of pulmonary fibrosis and emphysema at a significant extent despite of normal spirometric result. CONCLUSIONS: Cluster analysis identified distinct phenotypes, which predicted prognosis of clinical outcome. Formula using quantitative CT values is useful to assess extent of pulmonary fibrosis and emphysema with normal lung function in patients with IPF.

Comparative safety for cardiovascular outcomes of DPP-4 inhibitors versus glimepiride in patients with type 2 diabetes: A retrospective cohort study.

Concerns about the cardiovascular safety of dipeptidyl peptidase-4 (DPP-4) inhibitors persist. This study sought to determine whether there is a differential risk of hospitalization for cardiovascular diseases (CVDs) between DPP-4 inhibitors and glimepiride.We conducted this retrospective cohort study by using the Korean National Health Insurance Service database from December 1, 2008, to December 31, 2013. The study subjects were new users of DPP-4 inhibitors or glimepiride for type 2 diabetes. Outcome was defined as hospitalization for CVDs, including angina pectoris, myocardial infarction, transient cerebral ischemic attack, heart failure, or cerebrovascular disease or any procedure involving coronary artery bypass grafting or percutaneous coronary intervention. We used a Cox proportional hazard model to estimate the adjusted hazard ratios (aHRs) and their 95% confidence intervals (CIs), to assess the risk of CVDs associated with the use of DPP-4 inhibitors compared with glimepiride.The cohort consisted of 1,045,975 patients, with 6504 in the DPP-4 inhibitors group and 13,447 in the glimepiride group. No significant increased risk of total CVDs was found (aHR, 0.87; 95% CI, 0.75-1.01) in the DPP-4 inhibitors versus glimepiride group. A decreased risk of hospitalization for CVDs was found among patients with a history of visit for CVDs (aHR, 0.73; 95% CI, 0.56-0.97) or with >2.5 years' duration of type 2 diabetes (aHR, 0.77; 95% CI, 0.66-0.91) in the DPP-4 inhibitors versus glimepiride group.DPP-4 inhibitors did not increase cardiovascular risk compared with glimepiride regardless of CVD history and diabetes duration.

Health Care Utilization and Direct Costs in Mild, Moderate, and Severe Adult Asthma: A Descriptive Study Using the 2014 South Korean Health Insurance Database.

PURPOSE: Although asthma exacerbation comprises a large burden of the total asthma-related costs, few studies have examined the frequency and cost of acute exacerbation according to asthma severity. This study investigated asthma-related health care utilization and costs according to the severity of asthma. METHODS: We conducted a descriptive study using the national health insurance claims database between January 1 and December 31, 2014. We included adult patients with asthma (18 years of age and older) who had ≥2 claims with for an asthma diagnosis and were prescribed ≥1 asthma medications. They were classified into 3 asthma severity levels (level 1 = mild, level 2 = moderate, and level 3 = severe), based on individual medication prescriptions. Acute exacerbation was defined as having a corticosteroid burst, an emergency department visit, or hospitalization. Health care utilization, acute exacerbation, and direct costs associated with asthma were compared according to asthma severity levels. FINDINGS: Of the 36,687 adult asthma patients, level 1 had the largest proportion of patients (81.2%), followed by level 2 (18.2%), and level 3 (0.6%). The average number of asthma-related outpatient visits was 4.5 for level 1, 7.2 for level 2, and 11.9 for level 3 (P < 0.01). The estimated asthma-related direct cost per patient was $174 for level 1, $634 for level 2, and $1635 for level 3 (P < 0.01). The number of patients who experienced acute exacerbation increased as asthma severity increased: level 1, 22.6%; level 2, 26.0%; and level 3, 48.7% (P < 0.01). Direct costs associated with asthma exacerbation dramatically increased and accounted for 15.1% of the total cost in level 1 patients, 19.5% in level 2 patients, and 40.8% in level 3 patients (P < 0.01). IMPLICATIONS: The direct costs of acute exacerbation increased as asthma severity increased. In patients with severe asthma, acute exacerbation and the relative cost ratio in South Korea were higher than those in other countries. Proper management is required to avoid acute exacerbations and to reduce the burden of asthma, particularly in patients with severe asthma.