Tenapanor for peritoneal dialysis patients with hyperphosphatemia: a phase 3 trial.

BACKGROUND: Tenapanor is a novel selective inhibitor of intestinal sodium/hydrogen exchanger 3 transporter. This is the first trial to assess the efficacy and safety of tenapanor in Japanese patients with hyperphosphatemia who are undergoing peritoneal dialysis. METHODS: This phase 3, open-label, multicenter, single-arm clinical trial targeted patients whose serum phosphorus was within 3.5-7.0 mg/dL with phosphate binders at screening. After phosphate binder washout, tenapanor was orally administered twice-daily, stepwise from 5 to 30 mg/dose for 16 weeks. The primary endpoint, mean change in serum phosphorus level, was evaluated at week 8. The 16-week treatment period was completed with tenapanor alone, and only one phosphate binder type was allowed for combined use after the primary endpoint. RESULTS: Of the 54 patients enrolled, 34 completed the study. At week 8, the primary endpoint, mean change in serum phosphorus level (last observation carried forward), was - 1.18 mg/dL (95% confidence interval: - 1.54, - 0.81 mg/dL) with tenapanor. From a baseline value of 7.65 mg/dL, serum phosphorus decreased to 6.14 and 5.44 mg/dL at weeks 8 and 16, respectively, and 46.3% and 76.5% of patients achieved serum phosphorus within 3.5-6.0 mg/dL at week 8 and week 16, respectively. The most common adverse event, diarrhea, occurred in 74.1% of patients; the severity of diarrhea was mild or moderate. Thus, the discontinuation percentage due to diarrhea was low at 5.6%. CONCLUSIONS: Administration of tenapanor resulted in a sufficient reduction in serum phosphorus level at week 8 and was considered safe and tolerable. TRIAL REGISTRATION: NCT04766385.

[Changes in the neighborhood food environment and walking time among older adults: A longitudinal Japan Gerontological Evaluation Study (JAGES) between 2016 and 2019].

Objective　Maintaining or increasing walking provides several health benefits to older adults. However, the mid-term evaluation of Health Japan 21 [second term] showed that older adults' daily steps did not meet the goal. Therefore, this study emphasized primordial prevention, which is different from previous preventive approaches and focuses on the relationship between the built environment and physical activities, including daily steps. This study investigated the relationship between changes in the number of food stores and walking time.Methods　This longitudinal study utilized the self-administered mail survey data between 2016 and 2019 from the Japan Gerontological Evaluation Study (JAGES). Older adults aged ≥65 years and residing in 27 independent municipalities were recruited. The dependent variable was a change in the walking time at two-time points (increase or not). Our explanatory variable was the change in the number of food stores at two-time points, reported on a 5-point scale, including no store (reference), increased stores, store available, decreased stores, and I don't know. Equivalently, it was defined as the self-reported change in the number of food stores (stores that sell meats, fish, fruits, and vegetables) within the walking distance of participants' homes (within ～1 km) from 2016 to 2019. The covariates included demographic factors, health behavior factors, environmental factors, and health factors in 2016. We used Poisson regression analysis (5% significance level) to calculate the cumulative incidence rate ratio (CIRR) and 95% confidence interval (CI) for an increase in walking time compared to no increase in walking time. The multivariate normal imputation method supplemented missing data of the dependent variable, explanatory variable, and covariates. Additionally, respondents' answer of "other" for the covariates was supplemented.Results　Three years later, 13,400 (20.4%) respondents had increased their walking time. Older adults who reported increased number of stores (5,311, 8.1%) had more walking time than those who reported no stores (6,577, 10.0%) (CIRR=1.12; 95% CI: 1.03-1.21).Conclusion　Participants who reported an increase in the number of fresh food stores within the walking distance had 12% more walking time three years later. A built environment might be used to measure primordial prevention that increases the amount of walking in daily life. Our results may provide evidence for policymakers and stakeholders to consider healthy urban planning.

Fatty acid-binding protein 5 limits the generation of Foxp3+ regulatory T cells through regulating plasmacytoid dendritic cell function in the tumor microenvironment.

Plasmacytoid dendritic cells (pDCs) promote viral elimination by producing large amounts of Type I interferon. Recent studies have shown that pDCs regulate the pathogenesis of diverse inflammatory diseases, such as cancer. Fatty acid-binding protein 5 (FABP5) is a cellular chaperone of long-chain fatty acids that induce biological responses. Although the effects of FABP-mediated lipid metabolism are well studied in various immune cells, its role in pDCs remains unclear. This study, which compares wild-type and Fabp5-/- mice, provides the first evidence that FABP5-mediated lipid metabolism regulates the commitment of pDCs to inflammatory vs tolerogenic gene expression patterns in the tumor microenvironment and in response to toll-like receptor stimulation. Additionally, we demonstrated that FABP5 deficiency in pDCs affects the surrounding cellular environment, and that FABP5 expression in pDCs supports the appropriate generation of regulatory T cells (Tregs). Collectively, our findings reveal that pDC FABP5 acts as an important regulator of tumor immunity by controlling lipid metabolism.

DUV coherent light emission from ultracompact microcavity wavelength conversion device.

A unique design of our ultracompact microcavity wavelength conversion device exploits the simple principle that the wavelength conversion efficiency is proportional to the square of the electric field amplitude of enhanced pump light in the microcavity, and expands the range of suitable device materials to include crystals that do not exhibit birefringence or ferroelectricity. Here, as a first step toward practical applications of all-solid-state ultracompact deep-ultraviolet coherent light sources, we adopted a low-birefringence paraelectric SrB4O7 crystal with great potential for wavelength conversion and high transparency down to 130 nm as our device material, and demonstrated 234 nm deep-ultraviolet coherent light generation, whose wavelength band is expected to be used for on-demand disinfection tools that can irradiate the human body.

Functional Analysis of the Transcriptional Regulator IκB-ζ in Intestinal Homeostasis.

BACKGROUND: The Toll-like receptor signaling pathway contributes to the regulation of intestinal homeostasis through interactions with commensal bacteria. Although the transcriptional regulator IκB-ζ can be induced by Toll-like receptor signaling, its role in intestinal homeostasis is still unclear. AIMS: To investigate the role of IκB-ζ in gut homeostasis. METHODS: DSS-administration induced colitis in control and IκB-ζ-deficient mice. The level of immunoglobulins in feces was detected by ELISA. The immunological population in lamina propria (LP) was analyzed by FACS. RESULTS: IκB-ζ-deficient mice showed severe inflammatory diseases with DSS administration in the gut. The level of IgM in the feces after DSS administration was less in IκB-ζ-deficient mice compared to control mice. Upon administration of DSS, IκB-ζ-deficient mice showed exaggerated intestinal inflammation (more IFN-g-producing CD4+ T cells in LP), and antibiotic treatment canceled this inflammatory phenotype. CONCLUSION: IκB-ζ plays a crucial role in maintaining homeostasis in the gut.

Reduced atrial conduction velocity is associated with the recurrence of atrial fibrillation after catheter ablation.

The recurrence of atrial fibrillation (AF) after catheter ablation (CA) is still an unsolved issue. Although structural remodeling is relatively well defined, the method to assess electrical remodeling of the atrium is not well established. In this study, we evaluated the relationship between atrial conduction properties and recurrence after CA for AF. One hundred six consecutive patients (66 ± 11 years old, male: 68%) who underwent CA for AF with a CARTO system from July 2016 to July 2019 were enrolled in this study. An activation map of both atria was constructed to precisely evaluate the total conduction time, distance, and conduction velocity between the earliest and latest activation sites during sinus rhythm. All parameters were compared between the patients with or without AF recurrence. Of the patients, 27 had an AF recurrence (Rec group). The left atrial (LA) conduction velocity was significantly slower in the Rec group than in the non-Rec group (101.2 ± 17.9 vs. 116.9 ± 18.0 cm/s, P < 0.01). Likewise, the right atrial (RA) conduction velocity was significantly slower in the Rec group than in the non-Rec group (81.1 ± 17.5 vs. 103.6 ± 25.4 cm/s, P < 0.01). A multivariate logistic analysis demonstrated that the LA and RA conduction velocities were independent predictors of AF recurrence, with adjusted odds ratios of 0.95 (95% confidential interval: 0.91-0.98, P < 0.01) and 0.94 (0.89-0.98, P < 0.01), respectively. In conclusion, slower conduction velocity of the atrium was associated with AF recurrence after pulmonary vein isolation.

Curcumin analog GO-Y030 boosts the efficacy of anti-PD-1 cancer immunotherapy.

Regulatory T cells (Tregs) in the tumor microenvironment regulate tumor immunity. Programmed cell death protein 1 (PD-1) is known to be expressed on Tregs and plays crucial roles in suppressing tumor immunity. However, the immune checkpoint inhibitor, anti-PD-1 antibody, is known to promote the proliferation of the Treg population in tumor-infiltrating lymphocytes, thereby restricting the efficacy of cancer immunotherapy. In this study, we focused on the curcumin analog GO-Y030, an antitumor chemical. GO-Y030 inhibited the immune-suppressive ability of Tregs via metabolic changes in vitro, even in the presence of immune checkpoint inhibitors. Mechanistically, GO-Y030 inhibited the mTOR-S6 axis in Tregs, which plays a pivotal role in their immune-suppressive ability. GO-Y030 also controlled the metabolism in cultured CD4+ T cells in the presence of TGF-ß + IL-6; however, it did not prevent Th17 differentiation. Notably, GO-Y030 significantly inhibited IL-10 production from Th17 cells. In the tumor microenvironment, L-lactate produced by tumors is known to support the suppressive ability of Tregs, and GO-Y030 treatment inhibited L-lactate production via metabolic changes. In addition, experiments in the B16-F10 melanoma mouse model revealed that GO-Y030 helped inhibit the anti-PD-1 immune checkpoint and reduce the Treg population in tumor-infiltrating lymphocytes. Thus, GO-Y030 controls the metabolism of both Tregs and tumors and could serve as a booster for anti-immune checkpoint inhibitors.

Fatty acid-binding protein 3 controls contact hypersensitivity through regulating skin dermal Vγ4+ γ/δ T cell in a murine model.

BACKGROUND: Fatty acid-binding protein 3 (FABP3) is a cytosolic carrier protein of polyunsaturated fatty acids (PUFAs) and regulates cellular metabolism. However, the physiological functions of FABP3 in immune cells and how FABP3 regulates inflammatory responses remain unclear. METHODS: Contact hypersensitivity (CHS) induced by 2,4-dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin wild-type and Fabp3-/- mice. Skin inflammation was assessed using FACS, histological, and qPCR analyses. The development of γ/δ T cells was evaluated by a co-culture system with OP9/Dll1 cells in the presence or absence of transgene of FABP3. RESULTS: Fabp3-deficient mice exhibit a more severe phenotype of contact hypersensitivity (CHS) accompanied by infiltration of IL-17-producing Vγ4+ γ/δ T cells that critically control skin inflammation. In Fabp3-/- mice, we found a larger proportion of Vγ4+ γ/δ T cells in the skin, even though the percentage of total γ/δ T cells did not change at steady state. Similarly, juvenile Fabp3-/- mice also contained a higher amount of Vγ4+ γ/δ T cells not only in the skin but in the thymus when compared with wild-type mice. Furthermore, thymic double-negative (DN) cells expressed FABP3, and FABP3 negatively regulates the development of Vγ4+ γ/δ T cells in the thymus. CONCLUSIONS: These findings suggest that FABP3 functions as a negative regulator of skin inflammation through limiting pathogenic Vγ4+ γ/δ T-cell generation in the thymus.

IQ motif-containing GTPase-activating protein 1 is essential for the optimal maintenance of lung ILC2s.

Group 2 innate lymphoid cells (ILC2s) play critical roles in type 2 immunity and are crucial for pathogenesis of various types of inflammatory disease. IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffold protein that is involved in multiple cellular functions such as cell survival and trafficking. While the roles for IQGAP1 in T and B lymphocytes have been uncovered, the physiological significance of IQGAP1 in innate lymphocytes remains to be elucidated. In the current study, we demonstrate that using bone marrow chimeras, the deficiency of IQGAP1 caused an impaired survival of lung ILC2s in a cell-intrinsic manner and that Iqgap1-/- mice displayed decreased accumulation of ILC2s after administration of papain and thereby reduced the pathology of the disease. Moreover, Iqgap1-/- ILC2s showed a significantly enhanced apoptosis as compared to wild-type ILC2s under both steady-state and inflammatory conditions. Together these results identify for the first time that IQGAP1 is essential for homeostasis of ILC2s in the lung.

Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome.

Nephrotic syndrome (NS) is a renal disease characterized by severe proteinuria and hypoproteinemia. Although several single-gene mutations have been associated with steroid-resistant NS, causative genes for steroid-sensitive NS (SSNS) have not been clarified. While seeking to identify causative genes associated with SSNS by whole-exome sequencing, we found compound heterozygous variants/mutations (c.524T>C; p.I175T and c.662G>A; p.R221H) of the interleukin-1 receptor accessory protein (IL1RAP) gene in two siblings with SSNS. The siblings' parents are healthy, and each parent carries a different heterozygous IL1RAP variant/mutation. Since IL1RAP is a critical subunit of the functional interleukin-1 receptor (IL-1R), we investigated the effect of these variants on IL-1R subunit function. When stimulated with IL-1ß, peripheral blood mononuclear cells from the siblings with SSNS produced markedly lower levels of cytokines compared with cells from healthy family members. Moreover, IL-1R with a variant IL1RAP subunit, reconstituted on a hematopoietic cell line, had impaired binding ability and low reactivity to IL-1ß. Thus, the amino acid substitutions in IL1RAP found in these NS patients are dysfunctional variants/mutations. Furthermore, in the kidney of Il1rap-/- mice, the number of myeloid-derived suppressor cells, which require IL-1ß for their differentiation, was markedly reduced although these mice did not show significantly increased proteinuria in acute nephrotic injury with lipopolysaccharide treatment. Together, these results identify two IL1RAP variants/mutations in humans for the first time and suggest that IL1RAP might be a causative gene for familial NS.

GITR controls intestinal inflammation by suppressing IL-15-dependent NK cell activity.

Glucocorticoid-induced TNFR family related gene (GITR) is a member of the TNFR superfamily that is expressed on cells of the immune system. Although the protective and pathogenic roles of GITR in T cell immunity are well characterized, the role of GITR in innate immunity in the intestinal tissues has not been well clarified. In this study, using a dextran sulfate sodium (DSS)-induced colitis model in mice, we found that GITR-deficiency rendered mice more susceptible to acute intestinal inflammation and that a significantly higher number of activated natural killer (NK) cells was accumulated in the colonic lamina propria of Gitr-/- mice as compared to wild-type mice. Additionally, Rag2-/- Gitr-/- mice, which lack T cells but have NK cells, also displayed more severe colonic inflammation than Rag2-/- mice. In contrast, an anti-GITR agonistic antibody significantly alleviated colitis in Rag2-/- mice. Engagement of GITR inhibited IL-15-mediated activating signaling events in NK cells, which include cell activation and proliferation, and production of cytokines and cytotoxic granules. Taken together, our results provide the first evidence that GITR negatively controls intestinal inflammation through NK cell functions.

Ligand Bound Fatty Acid Binding Protein 7 (FABP7) Drives Melanoma Cell Proliferation Via Modulation of Wnt/ß-Catenin Signaling.

PURPOSE: Fatty acid-binding protein 7 (FABP7) involved in intracellular lipid dynamics, is highly expressed in melanomas and associated with decreased patient survival. Several studies put FABP7 at the center of melanoma cell proliferation. However, the underlying mechanisms are not well deciphered. This study examines the effects of FABP7 on Wnt/ß-catenin signaling that enhances proliferation in melanoma cells. METHODS: Skmel23 cells with FABP7 silencing and Mel2 cells overexpressed with wild-type FABP7 (FABP7wt) and mutated FABP7 (FABP7mut) were used. Cell proliferation and migration were analyzed by proliferation and wound-healing assay, respectively. Transcriptional activation of the Wnt/ß-catenin signaling was measured by luciferase reporter assay. The effects of a specific FABP7 inhibitor, MF6, on proliferation, migration, and modulation of the Wnt/ß-catenin signaling were examined. RESULTS: FABP7 siRNA knockdown in Skmel23 decreased proliferation and migration, cyclin D1 expression, as well as Wnt/ß-catenin activity. Similarly, FABP7wt overexpression in Mel2 cells increased these effects, but FABP7mut abrogated these effects. Pharmacological inhibition of FABP7 function with MF6 suppressed FABP7-regulated proliferation of melanoma cells. CONCLUSION: These results suggest the importance of the interaction between FABP7 and its ligands in melanoma proliferation modulation, and the beneficial implications of therapeutic targeting of FABP7 for melanoma treatment.

TNF Receptor-Associated Factor 5 Limits Function of Plasmacytoid Dendritic Cells by Controlling IFN Regulatory Factor 5 Expression.

The physiological functions of TNF receptor-associated factor 5 (TRAF5) in the skin inflammation and wound healing process are not well characterized. We found that Traf5 -/- mice exhibited an accelerated skin wound healing as compared with wild-type counterparts. The augmented wound closure in Traf5 -/- mice was associated with a massive accumulation of plasmacytoid dendritic cells (pDCs) into skin wounds and an enhanced expression of genes related to wound repair at skin sites. In accordance with this result, adoptive transfer of Traf5 -/- pDCs, but not wild-type pDCs, into the injured skin area in wild-type recipient mice significantly promoted skin wound healing. The expression of skin-tropic chemokine receptor CXCR3 was significantly upregulated in Traf5-/- pDCs, and treatment with a CXCR3 inhibitor cancelled the promoted wound healing in Traf5-/- mice, suggesting a pivotal role of CXCR3 in pDC-dependent wound healing. Traf5 -/- pDCs displayed significantly higher expression of IFN regulatory factor 5 (IRF5), which correlated with greater induction of proinflammatory cytokine genes and CXCR3 protein after stimulation with TLR ligands. Consistently, transduction of exogeneous TRAF5 in Traf5-/- pDCs normalized the levels of abnormally elevated proinflammatory molecules, including IRF5 and CXCR3. Furthermore, knockdown of IRF5 also rescued the abnormal phenotypes of Traf5-/- pDCs. Therefore, the higher expression and induction of IRF5 in Traf5-/- pDCs causes proinflammatory and skin-tropic characteristics of the pDCs, which may accelerate skin wound healing responses. Collectively, our results uncover a novel role of TRAF5 in skin wound healing that is mediated by IRF5-dependent function of pDCs.

TRAF5 promotes plasmacytoid dendritic cell development from bone marrow progenitors.

The conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) originate from the same common dendritic cell precursor cells in the bone marrow. The pDCs produce large amounts of type 1 interferon in response to foreign nucleic acid and crucially contribute to host defense against viral infection. Tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) is a pivotal component of various TNF receptor signaling pathways in the immune system. Although the functions of TRAF5 in T and B lymphocytes have been well studied, its roles in pDCs remains to be fully elucidated. In this study, we show that the expression of TRAF5 supports the generation of pDCs in the bone marrow and also critically contributes to the homeostasis of the pDC subset in the periphery in a cell-intrinsic manner. Furthermore, we provide evidence that TRAF5 promotes the commitment of DC precursor cells toward pDC versus cDC subsets, which is regulated by the balance of transcription factors TCF4 and ID2. Together our findings reveal that TRAF5 acts as a positive regulator of pDC differentiation from bone marrow progenitors.

Mitochondrial dysfunction in GnRH neurons impaired GnRH production.

The onset establishment and maintenance of gonadotropin-releasing hormone (GnRH) secretion is an important phenomenon regulating pubertal development and reproduction. GnRH neurons as well as other neurons in the hypothalamus have high-energy demands and require a constant energy supply from their mitochondria machinery to maintain active functioning. However, the involvement of mitochondrial function in GnRH neurons is still unclear. In this study, we examined the role of NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4), a member of the mitochondrial complex 1, on GnRH neurons using Ndufs4-KO mice and Ndufs4-KO GT1-7 cells. Ndufs4 was highly expressed in GnRH neurons in the medial preoptic area (MPOA) and NPY/AgRP and POMC neurons in the arcuate (ARC) nucleus in WT mice. Conversely, there was a significant decrease in GnRH expression in MPOA and median eminence of Ndufs4-KO mice, followed by impaired peripheral endocrine system. In Ndufs4-KO GT1-7 cells, Gnrh1 expression was significantly decreased with or without stimulation with either kisspeptin or NGF, whereas, stimulation significantly increased Gnrh1 expression in control cells. In contrast, there was no difference in cell signaling activity including ERK and CREB as well as the expression of GPR54, TrkA and p75NTR, suggesting that Ndufs4 is involved in the transcriptional regulation system for GnRH production. These findings may be useful in understanding the mitochondrial function in GnRH neuron.

Precise Signals with a High-Density Grid Mapping Catheter Are Useful for an Entrainment Study.

Complex atrial tachycardias (ATs) after catheter ablation or a MAZE procedure is sometimes difficult to determine the circuits of the tachycardia. A high-density, grid-shapes mapping catheter has been launched, which can be useful for detecting the detail circuits of tachycardias on three-dimensional mapping systems. The signal quality is also important for performing electrophysiological studies (EPSs), such as entrainment mapping, to identify the circuit. This unique mapping catheter has 1 mm electrodes on 2.5 Fr shafts, which improve the signal quality. The high-quality intracardiac electrograms facilitate differentiating small critical potentials, which allows us to perform detailed entrainment mapping in targeted narrow areas. Here, we describe a patient with a perimetral AT with epi-endocardium breakthrough after a MAZE surgery and catheter ablation, which was treated successfully along with detailed entrainment mapping using the HD Grid. This catheter with high-quality signals could be a significant diagnostic tool for a classic EPS as well as for the construction of 3D mapping.

Prediction of Lethal Arrhythmic Events Through Remote Monitoring Using Heart Rate Variability Analysis in Patients with an Implantable Cardioverter Defibrillator.

We prospectively collected device and heart rate data through remote monitoring (RM) of patients with an implantable cardioverter defibrillator (ICD). The objective was to identify the predictors of lethal arrhythmic events (VT/VF).Thirty-three patients (mean age: 50 years) with ICDs [with functionality of heart rate variability (HRV) analysis] were divided into two groups [VT/VF (+), VT/VF (-) ]. Clinical, device (ventricular lead impedance; amplitude of ventricular electrogram), and HRV data were compared between the two groups. The NN interval-index (SDNNi) was calculated for every 5 minutes, and the mean, maximum, minimum, and standard deviation of SDNNi during the 24-hour period were used.During the observation period of 13 ± 10 months, 10 patients experienced VT/VF events. Total mean, max, and min SDNNi were higher in the VT/VF (+) than the VT/VF (-) group (132.9 ± 9.3 versus 93.5 ± 6.1, P = 0.0013; 214.6 ± 10.6 versus 167.0 ± 7.0, P = 0.0007; 71.2 ± 7.5 versus 43.9 ± 4.9, P = 0.0047). On logistic regression analysis, a total mean SDNNi of 100.1, max SDNNi of 185.0 and min SDNNi of 52.0 as cut-off values for prediction of a VT/VF event demonstrated significant receiver operating characteristic (ROC) curves (AUC = 0.86, P = 0.0007; AUC = 0.84, P = 0.0005; AUC = 0.78, P = 0.0030). The max ΔSDNNi, i.e., difference from baseline SDNNi, and min ΔSDNNi in 7 and 28 days preceding VT/VF events were significant predictors of VT/VF events.Time-domain HRV analysis through a RM system may help identify patients at high risk of lethal arrhythmic events; in addition, it may help predict the occurrence of lethal arrhythmic events in specific cases.

Burden of Implanted-Device-Detected Atrial High-Rate Episode Is Associated With Future Heart Failure Events　- Clinical Significance of Asymptomatic Atrial Fibrillation in Patients With Implantable Cardiac Electronic Devices.

BACKGROUND: The relationship between atrial high-rate episode (AHRE) burden (i.e., the frequency of atrial tachyarrhythmia) and heart failure (HF) risk is unclear. We hypothesized that new-onset and higher burden of AHRE are associated with HF. Methods and Results: We included 104 consecutive patients with cardiac implantable electronic devices (CIEDs) capable of continuous atrial rhythm monitoring. Patients with AF history were excluded. To stratify patients, AHREs were evaluated only during the initial 1 year after CIED implantation. The primary endpoint was all-cause death or new-onset or worsening HF that required unplanned hospitalization or readjustment of HF drug therapy. At 1 year after CIED implantation, 34/104 patients (33%) exhibited AHREs. No difference in basal clinical characteristics except for left ventricular ejection fraction between patients with and without new-onset AHREs was found. AHRE groups had more HF events than the non-AHRE group. All patients were divided into 3 groups based on AHRE burden: none, low, and high. Worsening HF was observed in 12 patients (12%). Cox hazard analysis revealed that AHRE and higher AHRE burden were independent predictive factors for worsening HF. The high group showed a higher risk for HF than the non-AHRE groups, but no significant difference was found between the low- and non-AHRE groups. CONCLUSIONS: New-onset higher AHRE burden was associated with subsequent risk for HF in patients with CIEDs.

Combination index of the concentration and in vivo antagonism activity of racemic warfarin and its metabolites to assess individual drug responses.

The present study was undertaken to examine whether in vivo vitamin K epoxide reductase complex 1 (VKOR) "actual" antagonism activity, calculated by the concentrations and the reported anticoagulant activities of the R- and S-warfarin enantiomers and their metabolites, correlates with the weekly dose of warfarin. Five patients under palliative care were enrolled in our study and 20 serum samples were analyzed by an enantioselective high-performance liquid chromatography-ultraviolet detection method. In vivo VKOR inhibition activities of S-warfarin, R-warfarin, 7- and 10-hydroxywarfarin were calculated as the ratio of drug or metabolite concentration to the IC50. The mean drug concentrations (± SD) of S- and R-warfarin, 7-hydroxywarfarin and 10-hydroxywarfarin were 334 ± 154 ng/ml, 370 ± 115 ng/ml, 42 ± 15 ng/ml and 80 ± 44 ng/ml, respectively. Then, in vivo VKOR actual antagonism activities of S- and R-warfarin, 7-hydroxywarfarin and 10-hydroxywarfarin were calculated. Good correlation (R2 = 0.69-0.72) was obtained between the weekly warfarin dose and the ratios of INR/actual antagonism activity, while poor correlation was observed between the weekly warfarin dose and INR (R2 = 0.32) or the activities (R2 = 0.17-0.21). Actual antagonism activities along with the INR correlated well with the warfarin dose. This parameter may be useful for predicting or altering warfarin doses, although further verification in a larger study is required.

Real-World Antithrombotic Therapy in Atrial Fibrillation Patients with a History of Percutaneous Coronary Intervention.

Optimal antithrombotic strategy for atrial fibrillation (AF) patients with a history of percutaneous coronary intervention (PCI) has been under debate. The actual prescription trend of antithrombotic therapy for these patients remains unclear, especially in chronic phase.Patients with AF having at least a 1-year history of PCI were retrospectively evaluated in 2010, 2012, 2014, and 2016. A total of 266 patients were finally enrolled in this study. The proportion of patients prescribed with oral anticoagulants (OACs) gradually increased over the study period (56%, 67%, 73%, and 74% in 2010, 2012, 2014, and 2016, respectively). According to the type of OACs, the proportion of direct oral anticoagulant (DOAC), launched in 2011, increased compared with warfarin (DOAC versus warfarin = 3% versus 64% in 2012, 24% versus 49% in 2014, and 32% versus 42% in 2016). Single antiplatelet therapy (SAPT) with OAC was the most popular prescription every year, and its proportion increased over the study period (41%, 44%, 55%, and 59%, respectively). The proportion of OAC monotherapy gradually increased (2%, 3%, 8%, and 9%, respectively), whereas that of triple therapy, i.e., dual antiplatelet therapy with OAC, gradually decreased (14%, 22%, 8%, and 5% in 2010, 2012, 2014, and 2016, respectively).Antithrombotic therapy trends for AF patients with a history of PCI were changing every year. The prescription rate of triple therapy gradually decreased, in contrast, that of OAC monotherapy gradually increased from 2010 to 2016. However, the evidence for OAC monotherapy in these patients remains insufficient.