IMPORTANCE: Non–vitamin K oral anticoagulants (NOACs) are commonly prescribed with other medications that share metabolic pathways that may increase major bleeding risk. OBJECTIVE: To assess the ...association between use of NOACs with and without concurrent medications and risk of major bleeding in patients with nonvalvular atrial fibrillation. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study using data from the Taiwan National Health Insurance database and including 91 330 patients with nonvalvular atrial fibrillation who received at least 1 NOAC prescription of dabigatran, rivaroxaban, or apixaban from January 1, 2012, through December 31, 2016, with final follow-up on December 31, 2016. EXPOSURES: NOAC with or without concurrent use of atorvastatin; digoxin; verapamil; diltiazem; amiodarone; fluconazole; ketoconazole, itraconazole, voriconazole, or posaconazole; cyclosporine; erythromycin or clarithromycin; dronedarone; rifampin; or phenytoin. MAIN OUTCOMES AND MEASURES: Major bleeding, defined as hospitalization or emergency department visit with a primary diagnosis of intracranial hemorrhage or gastrointestinal, urogenital, or other bleeding. Adjusted incidence rate differences between person-quarters (exposure time for each person during each quarter of the calendar year) of NOAC with or without concurrent medications were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score. RESULTS: Among 91 330 patients with nonvalvular atrial fibrillation (mean age, 74.7 years SD, 10.8; men, 55.8%; NOAC exposure: dabigatran, 45 347 patients; rivaroxaban, 54 006 patients; and apixaban, 12 886 patients), 4770 major bleeding events occurred during 447 037 person-quarters with NOAC prescriptions. The most common medications co-prescribed with NOACs over all person-quarters were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%), and amiodarone (21.1%). Concurrent use of amiodarone, fluconazole, rifampin, and phenytoin with NOACs had a significant increase in adjusted incidence rates per 1000 person-years of major bleeding than NOACs alone: 38.09 for NOAC use alone vs 52.04 for amiodarone (difference, 13.94 99% CI, 9.76-18.13); 102.77 for NOAC use alone vs 241.92 for fluconazole (difference, 138.46 99% CI, 80.96-195.97); 65.66 for NOAC use alone vs 103.14 for rifampin (difference, 36.90 99% CI, 1.59-72.22); and 56.07 for NOAC use alone vs 108.52 for phenytoin (difference, 52.31 99% CI, 32.18-72.44; P < .01 for all comparisons). Compared with NOAC use alone, the adjusted incidence rate for major bleeding was significantly lower for concurrent use of atorvastatin, digoxin, and erythromycin or clarithromycin and was not significantly different for concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole, or posaconazole; and dronedarone. CONCLUSIONS AND RELEVANCE: Among patients taking NOACs for nonvalvular atrial fibrillation, concurrent use of amiodarone, fluconazole, rifampin, and phenytoin compared with the use of NOACs alone, was associated with increased risk of major bleeding. Physicians prescribing NOAC medications should consider the potential risks associated with concomitant use of other drugs.
Purpose
We aimed to evaluate the validity of cancer diagnosis in the National Health Insurance (NHI) database, which has routinely collected the health information of almost the entire Taiwanese ...population since 1995, compared with the Taiwan National Cancer Registry (NCR).
Methods
There were 26,542,445 active participants registered in the NHI database between 2001 and 2012. National Cancer Registry and NHI database records were compared for cancer diagnosis; date of cancer diagnosis; and 1, 2, and 5 year survival. In addition, the 10 leading causes of cancer deaths in Taiwan were analyzed.
Results
There were 908,986 cancer diagnoses in NCR and NHI database and 782,775 (86.1%) in both, with 53,192 (5.9%) in the NHI database only and 73,019 (8.0%) in the NCR only. The positive predictive value of the NHI database cancer diagnoses was 94% for all cancers; the positive predictive value of the 10 specific cancers ranged from 95% (lung cancer) to 82% (cervical cancer). The date of diagnosis in the NHI database was generally delayed by a median of 15 days (interquartile range 8‐18) compared with the NCR. The 1, 2, and 5 year survival rates were 71.21%, 60.85%, and 47.44% using the NHI database and were 71.18%, 60.17%, and 46.09% using NCR data.
Conclusions
Recording of cancer diagnoses and survival estimates based on these diagnosis codes in the NHI database are generally consistent with the NCR. Studies using NHI database data must pay careful attention to eligibility and record linkage; use of both sources is recommended.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Enhancer elements are a key regulatory feature of many important genes. Several general features including the presence of specific histone modifications are used to demarcate potentially active ...enhancers. Here we reveal that putative enhancers marked with H3 lysine 79 (H3K79) di or trimethylation (me2/3) (which we name H3K79me2/3 enhancer elements or KEEs) can be found in multiple cell types. Mixed lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major cause of incurable acute lymphoblastic leukemias (ALL). Using the DOT1L inhibitor EPZ-5676 in MLL-AF4 leukemia cells, we show that H3K79me2/3 is required for maintaining chromatin accessibility, histone acetylation and transcription factor binding specifically at KEEs but not non-KEE enhancers. We go on to show that H3K79me2/3 is essential for maintaining enhancer-promoter interactions at a subset of KEEs. Together, these data implicate H3K79me2/3 as having a functional role at a subset of active enhancers in MLL-AF4 leukemia cells.
This study examined whether the presence of product information focused on a past era (e.g., year of establishment) improved consumers' evaluations of a shop serving traditional products when the ...label and shop were congruent in terms of temporal focus. Across five experiments, participants viewed and evaluated advertisements from traditional food restaurants and shops that showed an old year of establishment. They showed favorable evaluations of the restaurants and food shops more frequently when a label focused on the past was displayed than when the label was absent or when a label focused on the present was displayed. Subsequent experiments indicated that this labeling effect was strongest when the label and shop were consistent in terms of traditional culture such that the year of establishment on the label showed the Japanese era name (Japan's traditional date format) and was accompanied by Japanese classic foods. Importantly, in this study, qualitative domains were consistently improved more often than were ratings of visit intention and expected taste. The results suggest that temporal congruence between the label and restaurants rated plays an essential role in ensuring that these advertisements are effective in improving positive evaluations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Connexin, a four-pass transmembrane protein, contributes to assembly of gap junctions among neighboring cells and thus facilitates gap junctional intercellular communication (GJIC). Traditionally, ...the roles of connexins were thought to mediate formation of hemichannels and GJIC assembly for transportation of ions and small molecules. Many studies have observed loss of GJIC, due to reduced expression or altered cytoplasmic localization of connexins, in primary tumor cells. Connexins are generally considered tumor-suppressive. However, recent studies of clinical samples suggested a different role of connexins in that expression levels and membrane localization of connexins, including Connexin 43 (Cx43, GJA1) and Connexin 26 (Cx26, GJB2), were found to be enhanced in metastatic lesions of cancer patients. Cx43- and Cx26-mediated GJIC was found to promote cancer cell migration and adhesion to the pulmonary endothelium. Regulatory circuits involved in the induction of connexins and their functional effects have also been reported in various types of cancer. Connexins expressed in stromal cells were correlated with metastasis and were implicated in regulating metastatic behaviors of cancer cells. Recent studies have revealed that connexins can contribute to cellular phenotypes via multiple ways, namely 1) GJIC, 2) C-terminal tail-mediated signaling, and 3) cell-cell adhesion during gap junction formation. Both expression levels and the subcellular localization could participate determining the functional roles of connexins in cancer. Compounds targeting connexins were thus tested as potential therapeutics intervening metastasis or chemoresistance. This review focuses on the recent findings in the correlation between the expression of connexins and patients' prognosis, their roles in metastasis and chemoresistance, as well as the implications and concerns of using connexin-targeting drugs as anti-metastatic therapeutics. Overall, connexins may serve as biomarkers for cancer prognosis and as therapeutic targets for intervening metastasis and chemoresistance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Increased Crabp2 levels have been found in various types of cancer, and are associated with poor patients' survival. Although Crabp2 is found to be overexpressed in lung cancer, its role in ...metastasis of lung cancer is unclear. In this study, Crabp2 was overexpressed in high-metastatic C10F4 than low-metastatic lung cancer cells. Analysis of clinical samples revealed that high CRABP2 levels were correlated with lymph node metastases, poor overall survival, and increased recurrence. Knockdown of Crabp2 decreased migration, invasion, anoikis resistance, and in vivo metastasis. Crabp2 was co-immunoprecipitated with HuR, and overexpression of Crabp2 increased HuR levels, which promoted integrin β1/FAK/ERK signaling. Inhibition of HuR or integrin β1/FAK/ERK signaling reversed the promoting effect of Crabp2 in migration, invasion, and anoikis resistance. Knockdown of Crabp2 further inhibited the growth of cancer cells as compared with that by gemcitabine or irinotecan alone. The expression of Crabp2 in human lung tumors was correlated with stress marker CHOP. In conclusion, our findings have identified the promoting role of Crabp2 in anoikis resistance and metastasis. CRABP2 may serve as a prognostic marker and targeting CRABP2 may be exploited as a modality to reduce metastasis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Novel norcorroles complexes with a phenyl‐substituted phosphorus center were synthesized by a template method and characterized by NMR spectroscopy and X‐ray single crystal diffraction. It was proved ...that these new norcorrole phosphorus complexes have aromaticity similar to the very recently reported norcorrole complex with a methoxy‐substituted phosphorus center. This aromaticity results from the peripheral 18π‐system consisting of two methine carbons and four amine‐type pyrrole units with formally pentavalent phosphorus center. On the other hand, these phenyl‐substituted phosphorus complexes showed quite characteristic and strong Q‐band derived from less symmetricity of the molecules than other porphyrinoids.
Novel norcorrole complexes with a phenyl‐substituted phosphorus center were synthesized as the new examples of norcorrole main‐group element complexes. These phosphorus complexes were found to have aromaticity resulting from the peripheral 18‐electron π‐conjugated system. Moreover, the phenyl‐substituted phosphorus complex exhibited unique optical properties such as a stronger Q‐band than Soret‐band and a fluorescent emission with significantly small Stokes shift.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The human visual system can actively prioritize task-relevant features to search for a target. Recent studies have reported cases in which the system may suppress irrelevant features by using a ...template for rejection. However, in those studies, the templates used for rejection were limited to the color domain, and they have yielded mixed results. Our literature review identified three differences among studies that may be responsible for such mixed results: differences in the spatial segmentation of items (i.e., segregated or intermixed across the display), differences in how features are defined and reported (i.e., combined or separate), and differences in cue lead times (short or long). Participants searched for a target-line segment in a shape and identified its orientation from among non-target line-shaped compound shapes that were preceded by one of three cue displays. Positive cues indicated that the target segment would appear in a shape, and negative cues that it would not appear in a shape. Neutral cues indicated that a particular shape would not appear in the current search display. The results demonstrated that reaction times were faster under the negative-cue condition than the neutral-cue condition, reflecting the effect of a shape-based template for rejection (Experiment
1
). Experiment
2
replicated the absence of the effect in the shape domain. Experiment
3
indicated that the template-for-rejection effect occurred only when the cue lead time was relatively long, suggesting that time is required (approximately 2,400 ms or longer) for the visual system to form rejection templates. Experiment
4
excluded the possibility that a confound in the target-defining/reporting feature was involved. These results indicated that apparent inconsistencies in research on the template-for-rejection effect can be explained in terms of the time required for templates to be configured.
Early detection of coagulopathy is important to prevent bleeding during liver transplantation (LT). Rotation thromboelastometry (ROTEM®) provides the earliest parameter of clot amplitudes at 5 min ...(A5). We evaluated whether A5 correlates with platelet count (PLT) and fibrinogen concentration (Fib) and can predict thrombocytopenia and hypofibrinogenaemia in hypocoagulable patients undergoing living-donor LT (LDLT).
A total of 3446 retrospective ROTEM® measurements, including 1139 EXTEM, 1182 INTEM, and 1125 FIBTEM, with simultaneously measured PLT and Fib, were analysed during LDLT in 239 patients. The correlations between A5 and maximum clot firmness (MCF) index, PLT, and Fib were calculated. Receiver operating characteristic analysis with area under the curve (AUC) was used to assess A5 thresholds predictive of PLT and Fib.
The median PLT was 47 000 mm−3 and the median Fib was 100 mg dl−1 during LDLT. The A5 parameters of EXTEM (A5EXTEM) and INTEM (A5INTEM) were highly correlated with MCF (r=0.96 and r=0.95, respectively), PLT (r=0.76 and r=0.77, respectively), and Fib (r=0.63 and r=0.64, respectively). A5 of FIBTEM (A5FIBTEM) was also correlated with MCF (r=0.91) and Fib (r=0.75). A5EXTEM thresholds of 15 and 19 mm predicted PLT<30 000 mm−3 (AUC=0.90) and <50 000 mm−3 (AUC=0.87), respectively, whereas A5FIBTEM 4 mm predicted Fib<100 mg dl−1 (AUC=0.86). Biases from A5EXTEM and A5FIBTEM to their MCFs were 16.4 and 1.3 mm, respectively.
A5 as an early variable of clot firmness is effective in detecting critically low PLT and Fib. A5 can therefore be a reliable fast index guiding transfusion therapy in hypocoagulable patients undergoing LDLT.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
How high can public debt rise without compromising fiscal solvency? We answer this question using a stochastic model of sovereign default in which risk-neutral investors lend to a government that ...displays 'fiscal fatigue', whereby its ability to increase primary balances cannot keep pace with rising debt. As a result, the government faces an endogenous debt limit beyond which debt cannot be rolled over. Using data for 23 advanced economies over the period 1970—2007, we find evidence of a fiscal reaction function with these features, and use it to compute 'fiscal space', defined as the difference between current debt ratios and the estimated debt limits.
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BFBNIB, FZAB, GIS, IJS, INZLJ, IZUM, KILJ, NLZOH, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZRSKP
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