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.

Cost-effectiveness of improving patients' adherence to tuberculosis treatment in South Korea using discrete event simulation.

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.

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.

graph-GPA 2.0: improving multi-disease genetic analysis with integration of functional annotation data.

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.

Cost-Effectiveness of All-Oral Regimens for the Treatment of Multidrug-Resistant Tuberculosis in Korea: Comparison With Conventional Injectable-Containing Regimens.

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.

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.

Health-related quality of life in adult patients with asthma according to asthma control and severity: A systematic review and meta-analysis.

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.

Real-world association of adherence with outcomes and economic burden in patients with tuberculosis from South Korea claims data.

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.

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 impact and economic burden of post-transplant infections following heart transplantation: A retrospective nationwide cohort study.

BACKGROUND: Post-transplant infections are associated with high mortality rates. This retrospective nationwide cohort study examined the incidence and risk factors of infections requiring hospitalization after heart transplantation and the associated economic burden. METHODS: The entire heart transplant recipients' data from the Korean Health Insurance Review and Assessment Service between 2013 and 2020 was used. We estimated the annual incidence of post-transplant infections and adjusted incidence rate ratios (aIRR) of risk factors for reported infections using the poisson generalized linear model. RESULTS: Among 1,030 heart transplant recipients (324 with and 706 without post-transplant infections), 0.45 post-transplant infections were reported annually, with respiratory tract infections constituting the highest proportion (0.16). The risk of post-transplant infections was high in recipients with renal failure (aIRR = 1.35; 95% confidence interval [CI], 1.05-1.75) or nosocomial infection (aIRR = 1.47; 95% CI, 1.15-1.87). Combination regimens, including mammalian target of rapamycin inhibitor (mTORi), did not differ significantly from the standard 3 drug regimen (aIRR = 1.16; 95% CI, 0.80-1.67). The risk of death was higher among recipients with post-transplant infections than in uninfected recipients (adjusted hazard ratio = 4.59; 95% CI, 2.19-9.65). The mean follow-up cost per patient per month was 2-fold higher in recipients with post-transplant infections than in uninfected recipients ($5,096 and $2,532, respectively; p < .001). CONCLUSIONS: mTORi combination, which reportedly maintains renal function, can be considered, as it does not increase the infection risk. Post-transplant infections present clinical and economic burdens, warranting careful observation of at-risk patients.

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.

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.

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.

Adherence is an optimal factor for maximizing the effective and safe use of oral anticoagulants in patients with atrial fibrillation.

Few studies assessed the association between major adverse cardiovascular events and adherence to warfarin and direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF). Therefore, we aimed to evaluate the effects of adherence to oral anticoagulants (OACs) in patients with AF using claims data (July 2014-April 2019). Using the initial 3-month medication possession rate (MPR), patients were categorized into adherent (MPR ≥ 0.8) or non-adherent (MPR < 0.8) groups. Propensity score matching of non-adherent group to adherent group was conducted for warfarin (1:1) and DOAC (1:3), respectively. Incidence of ischemic stroke, myocardial infarction (MI), intracranial hemorrhage, and all-cause death was assessed in the matched cohort (67,147 patients). The hazard ratio (HR) for adherence to OAC was estimated using the Cox proportional hazard model with adjusting covariate including age and sex. The risk for ischemic stroke, MI, and all-cause death was lower in the DOAC adherent group than in the DOAC non-adherent group (HR: 0.78; 95% confidence intervals: 0.73-0.84; 0.75, 0.60-0.94; 0.54, 0.51-0.57, respectively). Adherence to OAC was not associated with the risk of intracranial hemorrhage (1.01, 0.85-1.20). Commitment programs to improve adherence in patients with AF could maximize drug effectiveness and safety.

Carvone and its eutectic mixtures as novel, biodegradable, and tunable solvents to extract hydrophobic compounds in substitution for volatile toxic solvents.

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.

Trefoil factor 2 secreted from damaged hepatocytes activates hepatic stellate cells to induce fibrogenesis.

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.

Incidence and risk factors of subsequent osteoporotic fracture: a nationwide cohort study in South Korea.

This study analyzed the incidence and risk factors of subsequent osteoporotic fractures in South Korea. The results showed that the incidence rate of subsequent fractures within 24 months was 10.23 per 100 person-years. Additionally, the index hip fracture site was a significant risk factor for a subsequent fracture. PURPOSE: To identify and analyze the incidence and risk factors of subsequent osteoporotic fractures in South Korea. METHODS: This retrospective cohort study analyzed data from the National Health Insurance Review and Assessment claims database from 2012 to 2017. Men and women with osteoporosis, aged ≥50 years, with index fractures between July 1, 2014, and July 1, 2015, were included. The incidence rate of subsequent fractures was calculated by determining the number of second event within 2 years from the index fracture. To identify the risk factors for subsequent fractures, we applied the Cox proportional hazard model to estimate the hazard ratios (HRs). RESULTS: Of the 73,717 patients with osteoporotic fractures, 13,203 (17.91%) had a subsequent fracture. The incidence rate of subsequent fractures within 24 months was 10.23/100 person-years. The index fracture site was a significant risk factor for a subsequent fracture, with the hip showing the highest risk (HR, 7.51; 95% confidence interval [CI], 6.77-8.34), followed by the vertebra (HR, 1.99; 95% CI, 1.91-2.06). The risk of subsequent fractures increased with a higher Charlson Comorbidity Index (CCI) score (CCI score ≥ 5: HR, 1.79; 95% CI, 1.67-1.92). CONCLUSION: The incidence rate of subsequent osteoporotic fractures in South Korea is similar or higher than that reported in the USA and Europe. A hip fracture within the prior 2 years, relative to other fracture sites, significantly increased the risk of subsequent fractures in osteoporosis patients. Patients who have these risk factors need closer disease management to prevent subsequent fractures.

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.

Economic burden of subsequent fracture in osteoporosis patients in South Korea.

OBJECTIVES: This study aimed to assess the economic burden of subsequent fracture in osteoporosis patients with incident fracture. METHODS: The authors conducted a retrospective cohort analysis of the South Korean national health insurance claims data. Study subjects included osteoporosis patients aged ≥50 with incident fracture (July 1, 2014-June 30, 2015). Fracture-related 1-year healthcare cost was evaluated after incident fracture for patients with and without subsequent fracture, defined as a fracture occurring within 2 years from incident fracture at a different site or at the same site after 6-months washout period. Per-patient-per-month (PPPM) cost was calculated by dividing each patient's cumulative healthcare cost until subsequent fracture with time-to-subsequent-fracture. For the patients without subsequent fracture, PPPM cost equaled 1-year monthly cost. A generalized linear model (GLM) was used to estimate the ratio of increase in healthcare cost to assess the economic impact of subsequent fracture. RESULTS: A total of 73,717 osteoporosis patients with incident fracture were identified, consisting of 52.1% vertebral, 1.9% hip, and 46.0% non-vertebral-non-hip fractures. Subsequent fracture occurred in 17.9% of patients with average time-to-subsequent-fracture of 256 days. Patients with subsequent fracture had significantly higher 1-year healthcare cost after incident fracture than those without subsequent fracture ($4,307 vs $1,721) and the difference was greater in PPPM cost ($930 vs $141). GLM analysis showed that having subsequent fracture increased both 1-year healthcare cost and PPPM cost by 1.91-fold (95% CI = 1.87-1.95) and 6.14-fold (95% CI = 5.99-6.28), respectively. CONCLUSIONS: Subsequent fracture imposes a substantial burden on osteoporosis patients and, therefore, more efforts are needed for preventing subsequent fracture among osteoporosis patients.