Analysis of Selenoprotein F Binding to UDP-Glucose:Glycoprotein Glucosyltransferase (UGGT) by a Photoreactive Crosslinker.

In the endoplasmic reticulum glycoprotein quality control system, UDP-glucose : glycoprotein glucosyltransferase (UGGT) functions as a folding sensor. Although it is known to form a heterodimer with selenoprotein F (SelenoF), the details of the complex formation remain obscure. A pulldown assay using co-transfected SelenoF and truncated mutants of human UGGT1 (HUGT1) revealed that SelenoF binds to the TRXL2 domain of HUGT1. Additionally, a newly developed photoaffinity crosslinker was selectively introduced into cysteine residues of recombinant SelenoF to determine the spatial orientation of SelenoF to HUGT1. The crosslinking experiments showed that SelenoF formed a covalent bond with amino acids in the TRXL3 region and the interdomain between ßS2 and GT24 of HUGT1 via the synthetic crosslinker. SelenoF might play a role in assessing and refining the disulfide bonds of misfolded glycoproteins in the hydrophobic cavity of HUGT1 as it binds to the highly flexible region of HUGT1 to reach its long hydrophobic cavity. Clarification of the SelenoF-binding domain of UGGT and its relative position will help predict and reveal the function of SelenoF from a structural perspective.

Blood glucose trends in glycogen storage disease type Ia: A cross-sectional study.

BACKGROUND: Glycogen storage disease type Ia (GSDIa) is caused by biallelic pathogenic variants in the glucose-6-phosphatase gene (G6PC) and mainly characterized by hypoglycemia, hepatomegaly, and renal insufficiency. Although its symptoms are reportedly mild in patients carrying the G6PC c.648G>T variant, the predominant variant in Japanese patients, details remain unclear. Therefore, we examined continuous glucose monitoring (CGM) data and daily nutritional intake to clarify their associations in Japanese patients with GSDIa with G6PC c.648G>T. METHODS: This cross-sectional study enrolled 32 patients across 10 hospitals. CGM was performed for 14 days, and nutritional intake was recorded using electronic diaries. Patients were divided according to genotype (homozygous/compound heterozygous) and age. The durations of biochemical hypoglycemia and corresponding nutritional intake were analyzed. Multiple regression analysis was performed to identify factors associated with the duration of biochemical hypoglycemia. RESULTS: Data were analyzed for 30 patients. The mean daily duration of hypoglycemia (<4.0 mmol/L) in the homozygous group increased with age (2-11 years [N = 8]: 79.8 min; 12-18 years [5]: 84.8 min; ≥19 years [10]: 131.5 min). No severe hypoglycemic symptoms were recorded in the patients' diaries. The mean frequency of snack intake was approximately three times greater in patients aged 2-11 years (7.1 times/day) than in those aged 12-18 years (1.9 times/day) or ≥19 years (2.2 times/day). Total cholesterol and lactate were independently associated with the duration of biochemical hypoglycemia. CONCLUSION: Although nutritional therapy prevents severe hypoglycemia in patients with GSDIa with G6PC c.648G>T, patients often experience asymptomatic hypoglycemia.

Janus-Type Mixed-Valent Copper-Cyanido Honeycomb Layers.

The synthesis of Janus-type layers, which possess front and back sides that consist of different structures, remains a major challenge in the field of two-dimensional materials. In this study, two Janus-type layered coordination polymers, namely, CuII(NEtH2)(NMe2H·H2O)CuI(CN)3 (1) and CuII(NMe2H)(NMe2H·H2O)CuI(CN)3 (2), were synthesized via a simple one-pot procedure using copper(II) nitrate and sodium cyanido in mixed solutions of dimethylamine and ethylamine. Uniquely, 1 and 2 were composed of cyanido-bridged neutral layers and exhibited a CuICuII mixed-valent state. Meanwhile, using a solution of pure dimethylamine for the synthesis yielded the monovalent three-dimensional framework (NMe2H2)[CuI2(CN)3] (3). Results indicated that the simultaneous use of two mixed amines gave rise to the controlled reduction of CuII ions during the reaction. In addition, each face of the layers was coordinated by different amines on the axial positions of the CuII sites, resulting in anisotropic Janus layers. Furthermore, the thermal expansion behavior of 2 was investigated, demonstrating that the neutral [CuICuII(CN)3] layer was relatively rigid compared with the analogous anionic [CuI2(CN)3]- layer.

Prognosis of elderly non-valvular atrial fibrillation patients stratified by B-type natriuretic peptide: ELDERCARE-AF subanalysis.

BACKGROUND: B-type natriuretic peptide (BNP) is a risk factor for stroke and cardiac death in patients with atrial fibrillation. We hypothesized the prognostic outcomes of very elderly non-valvular atrial fibrillation patients ineligible for standard anticoagulation treatment would vary according to BNP stratification. METHODS: In this subanalysis of the ELDERCARE-AF trial, patients were stratified by BNP levels at enrollment, and clinical outcomes compared among BNP subgroups. Hazard ratios were adjusted for age, atrial fibrillation type, body mass index, creatine clearance, congestive heart failure, and D-dimer. BNP levels were measured using chemiluminescence enzyme immunoassays. RESULTS: In total, 984 patients (average age: 86.6 years) not considered eligible for oral anticoagulant therapy at approved doses for stroke prevention were included. The BNP levels at enrollment were <200 (low), 200 to <400 (moderate), and ≥400 (high) pg/mL in 428, 300, and 256 patients, respectively. The number (%) of patients with stroke or systemic embolism (SSE) was 7 (1.2%), 24 (5.9%), and 28 (8.6%) in the low, moderate, and high BNP subgroups, respectively (adjusted hazard ratio 3.82, P = .0025 for low vs moderate BNP and 4.76, P = .0007 for low vs high BNP). There was no significant difference in major bleeding incidence between the BNP subgroups. Edoxaban 15 mg was associated with a consistent reduction in SSE vs placebo in all BNP subgroups. CONCLUSIONS: Stratification by BNP level was associated with the incidence of SSE for very elderly non-valvular atrial fibrillation patients ineligible for standard anticoagulation treatment, and the effect of edoxaban 15 mg was consistent across BNP levels.

Effects of self-hydrogen bonding among formamide molecules on the UCST-type liquid-liquid phase separation of binary solutions with imidazolium-based ionic liquid, [Cnmim][TFSI], studied by NMR, IR, MD simulations, and SANS.

The upper critical solution temperature (UCST)-type liquid-liquid phase separation of imidazolium-based ionic liquids (ILs), 1-alkyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([Cnmim][TFSI], where n represents the alkyl chain length of the cation, n = 6, 8, 10, and 12) binary solutions with formamide (FA) was examined as a function of temperature and the FA mole fraction xFA. The two-phase region (immiscible region) of the solutions is much larger and expands more with the increase in n, in comparison with the previous [Cnmim][TFSI]-1,4-dioxane (1,4-DIO) systems. An array of spectroscopic techniques, including 1H and 13C NMR and IR combined with molecular dynamics (MD) simulations, was conducted on the present binary systems to clarify the microscopic interactions that contribute to the phase-separation mechanism. The hydrogen-bonding interactions of the imidazolium ring H atoms are more favorable with the O atoms of the FA molecules than with 1,4-DIO molecules, whereas the latter interact more favorably with the alkyl chain of the cation. Upon lowering the temperature, the FA molecules gradually self-aggregate through self-hydrogen bonding to form FA clusters. Concomitantly, clusters of ILs are formed via the electrostatic interaction between the counter ions and the dispersion force among the IL alkyl chains. Small-angle neutron scattering (SANS) experiments on the [C6mim][TFSI]-FA-d2 and [C8mim][TFSI]-FA-d2 systems revealed, similarly to [Cnmim][TFSI]-1,4-DIO systems, the crossover of the mechanism from the 3D-Ising mechanism around the UCST xFA to the mean-field mechanism at both sides of the mole fraction. Interestingly, the xFA range of the 3D-Ising mechanism for the FA systems is wider compared with the range of the 1,4-DIO systems. In this way, the self-hydrogen bonding among FA molecules most significantly governs the phase equilibria of the [Cnmim][TFSI]-FA systems.

Directing a dispersion cannula tip toward the aortic root during thoracic aortic arch surgery does not adversely affect cardiac function.

INTRODUCTION: Neurologic complications of open thoracic aortic surgery are devastating problems in patients with severely diseased aortas. This study aimed to clarify whether directing the aortic cannula tip toward the aortic root affects the postoperative cardiac function in patients undergoing open thoracic aortic surgery. METHODS: A total of 16 patients who underwent total or partial arch replacement between January 2014 and April 2019 were enrolled and divided into two groups. Ascending aorta perfusion was performed by placing the cannula tip toward the aortic root (reversed direction group, seven patients) or toward the aortic arch (standard direction group, nine patients). Intraoperative and perioperative data, including mortality, morbidity, and postoperative cardiac function, were compared between the groups. RESULTS: There were no hospital deaths or stroke events in either group. The aortic cross-clamping time was 102.4 ± 20.3 minutes in the reversed direction group and 87.1 ± 9.9 minutes in the standard direction group (p = 0.049). Furthermore, the intubation time was 28.4 ± 12.9 hours in the reversed direction group and 12.4 ± 6.8 hours in the standard direction group (p = 0.022). Both times were significantly longer in the reverse direction group. Postoperative serum creatine kinase-MB levels were significantly lower in the reversed direction group (6.2 ± 3.3 U/L vs 13.3 ± 4.8 U/L, respectively, p = 0.006). The cardiac output and cardiac index did not significantly differ. CONCLUSIONS: Directing the aortic cannula tip toward the aortic root does not adversely affect the postoperative cardiac function after aortic arch surgery.

Ruptured Abdominal Aortic Aneurysm Repair Using Open Proximal Anastomosis Under Deep Hypothermic Circulatory Arrest.

Proximal aortic clamping under normothermia is generally adequate for operative repair of abdominal aortic rupture; however, the hypothermic circulatory arrest (HCA) technique is not as common. Proximal exposure and clamping are sometimes difficult due to the risk of bleeding, rerupture, and ischemia. We present a successful case of a ruptured abdominal aortic aneurysm (AAA) that was repaired using cardiopulmonary bypass with HCA. A 75-year-old man presented with sudden back pain and was diagnosed with a ruptured AAA using computed tomography. The aneurysm had a maximal diameter of 100 mm and protruded anteriorly just below the renal arteries. The rupture site was close to the renal arteries, and thus, there was a high risk of bleeding and shock during proximal exposure. Cardiopulmonary bypass was established by cannulation of the right axillary artery and right femoral vein, following which open laparotomy was performed. Proximal exposure and anastomosis could be safely performed using HCA. This cardiopulmonary bypass with HCA technique may be useful as a surgical strategy for ruptured juxta-renal AAAs.

Coronary artery bypass grafting after sternal turnover procedure and a review of the literature.

We report a case of complete revascularization after a sternal turnover procedure through median sternotomy in a patient with multivessel coronary artery disease. The patient had unusual anatomical features, such as the anterior protrusion of the middle-to-distal sternum and absent bilateral internal thoracic arteries (ITAs). The single-blade sternum retractor and the Omni-Tract retractors are simple and reliable tools for lifting and widening the thoracic wall around the xiphoid process. The bilateral radial arteries and the great saphenous vein were used as bypass grafts. Computed tomography was used to visualize the sternum supplied by the superior epigastric arteries (SEAs); presurgical abdominal ultrasonography revealed the course and crossing point of the developed SEAs. Since ITAs were absent, we preserved the SEAs to prevent sternal ischemia. No sternal complications or graft occlusion were observed during follow-up.

[Valve Re-replacement after Aortic Valve Replacement with Starr-Edwards Ball Valve Forty-five Years Ago:Report of a Case].

The patient was a 67-year-old man. At 22 years of age, he underwent aortic valve replacement with Starr-Edwards ball valve. At 67 years of age, he complained of fatigue of the New York Heart Association (NYHA) class Ⅲ condition. He was diagnosed with mitral regurgitation, tricuspid regurgitation, ascending aortic aneurysm and chronic atrial fibrillation. Transthoracic and transesophageal echocardiograms showed a mobile, elongated echogenic mass attached to the valve cage and floating downstream. We performed Bentall procedure, ascending aortic replacement, mitral valve replacement, tricuspid annuloplasty and left atrial appendage closure. Explanted ball valve showed extensive cloth destruction and partial cloth tear. Mild pannus formation was observed beneath the valve. Despite 45 years after initial operation, significant valve dysfunction was not observed.

Transcription factor MafB in podocytes protects against the development of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a common cause of steroid-resistant nephrotic syndrome. Spontaneous remission of FSGS is rare and steroid-resistant FSGS frequently progresses to renal failure. Many inheritable forms of FSGS have been described, caused by mutations in proteins that are important for podocyte function. Here, we show that a basic leucine zipper transcription factor, MafB, protects against FSGS. MAFB expression was found to be decreased in the podocytes of patients with FSGS. Moreover, conditional podocyte-specific MafB-knockout mice developed FSGS with massive proteinuria accompanied by depletion of the slit diaphragm-related proteins (Nphs1 and Magi2), and the podocyte-specific transcription factor Tcf21. These findings indicate that MafB plays a crucial role in the pathogenesis of FSGS. Consistent with this, adriamycin-induced FSGS and attendant proteinuria were ameliorated by MafB overexpression in the podocytes of MafB podocyte-specific transgenic mice. Thus, MafB could be a new therapeutic target for FSGS.

Transthyretin Concentrations in Acute Stroke Patients Predict Convalescent Rehabilitation.

OBJECTIVE: For stroke patients, intensive nutritional management is an important and effective component of inpatient rehabilitation. Accordingly, acute care hospitals must detect and prevent malnutrition at an early stage. Blood transthyretin levels are widely used as a nutritional monitoring index in critically ill patients. Here, we had analyzed the relationship between the transthyretin levels during the acute phase and Functional Independence Measure in stroke patients undergoing convalescent rehabilitation. METHODS: We investigated 117 patients who were admitted to our hospital with acute ischemic or hemorrhagic stroke from February 2013 to October 2015 and subsequently transferred to convalescent hospitals after receiving acute treatment. Transthyretin concentrations were evaluated at 3 time points as follows: at admission, and 5 and 10 days after admission. After categorizing patients into 3 groups according to the minimum transthyretin level, we analyzed the association between transthyretin and Functional Independence Measure. RESULTS: In our patients, transthyretin levels decreased during the first 5 days after admission and recovered slightly during the subsequent 5 days. Notably, Functional Independence Measure efficiency was significantly associated with the decrease in transthyretin levels during the 5 days after admission. Patients with lower transthyretin levels had poorer Functional Independence Measure outcomes and tended not to be discharged to their own homes. DISCUSSION: A minimal transthyretin concentration (<10 mg/dL) is predictive of a poor outcome in stroke patients undergoing convalescent rehabilitation. In particular, an early decrease in transthyretin levels suggests restricted rehabilitation efficiency. Accordingly, transthyretin levels should be monitored in acute stroke patients to indicate mid-term rehabilitation prospects.

Differential expression patterns of MafB and c-Maf in macrophages in vivo and in vitro.

The large Maf transcription factors c-Maf and MafB are expressed in macrophage-lineage hematopoietic cells, but the expression patterns of MafB and c-Maf in macrophage subtypes and tissue-resident macrophages have not been fully analyzed. First, we analyzed MafB and c-Maf protein expression in tissue-resident macrophages. Mouse lymph nodes, spleens, lungs, and kidneys were subjected to immunohistochemistry using anti-MafB and anti-c-Maf. Both MafB and c-Maf signals were observed in lymph node macrophages. In the splenic macrophages the MafB signal was detected by anti-MafB, but the c-Maf signal was not detected. No expression of c-Maf or MafB was detected in macrophages in the lung and kidney. Flow cytometry analysis revealed a similar pattern of GFP expression in Mafb/GFP knock-in heterozygous mice. To analyze these different expression patterns in greater detail, we examined the expression of MafB and c-Maf by quantitative RT-PCR in different cytokine- or LPS-induced macrophages in vitro. MafB expression was induced by IL-10 or IL-4 with IL-13 and was reduced by LPS or GM-CSF. By contrast, c-Maf expression was induced by IL-10 and reduced by IL-4 with IL-13 or GM-CSF. These results indicate that MafB and c-Maf have different expression patterns in macrophages, suggesting differences in function.

Structurally Diverse Polyamines: Solid-Phase Synthesis and Interaction with DNA.

A versatile solid-phase approach based on peptide chemistry was used to construct four classes of structurally diverse polyamines with modified backbones: linear, partially constrained, branched, and cyclic. Their effects on DNA duplex stability and structure were examined. The polyamines showed distinct activities, thus highlighting the importance of polyamine backbone structure. Interestingly, the rank order of polyamine ability for DNA compaction was different to that for their effects on circular dichroism and melting temperature, thus indicating that these polyamines have distinct effects on secondary and higher-order structures of DNA.

Twenty-year experience following aortic valve replacement in patients younger than 60 years of age.

OBJECTIVE: Reports on long-term outcomes of surgical aortic valve replacement (AVR) for patients aged < 60 years are scarce in Japan. Hence, we aimed to evaluate these outcomes in patients aged < 60 years. METHODS: Between March 2000 and December 2020, 1477 patients underwent aortic valve replacement. In total, 170 patients aged < 60 years who underwent aortic valve replacement were recruited. Patients aged < 18 years were excluded. Patient data collected from the operative records and follow-up assessments were reviewed. RESULTS: The mean age was 49 ± 9 years, and 64.1% of patients were male. One-hundred-and-fifty-two patients (89.4%) underwent aortic valve replacement with a mechanical valve and 18 (10.6%) with a bioprosthetic valve. The mean follow-up period was 8.1 ± 5.5 years. No operative mortality occurred, and in-hospital mortality occurred in one patient (0.6%). Ten late deaths occurred, with seven cardiac-related deaths. The overall survival rate was 95.4 ± 1.7%, 93.9 ± 2.3%, 90.6 ± 3.9%, and 73.2 ± 11.8% at 5, 10, 15, and 20 years, respectively. Freedom from major bleeding was 96.4 ± 1.6% at 5, 10, and 15 years, and 89.0 ± 7.3% at 20 years. Freedom from thromboembolic events was 98.7 ± 1.3%, 97.3 ± 1.9%, 90.5 ± 4.5%, and 79.0 ± 11.3% at 5, 10, 15, and 20 years, respectively. Freedom from valve-related reoperation was 99.4 ± 0.6% at 5 years, 97.8 ± 1.7% at 10 and 15 years, and 63.9 ± 14.5% at 20 years. CONCLUSIONS: Patients aged < 60 years undergoing aortic valve replacement with a high mechanical valve implantation rate had favorable long-term outcomes.

A novel style of 2D Hofmann-type coordination polymer incorporated trigonal prismatic coordination geometry with bidentate co-ligands.

A novel 2D Hofmann-type framework was prepared with a bidentate co-ligand, 5,5'-dimethyl-2,2'-bipyridyl (dmbpy), which forces the curvature of the layer. X-ray diffraction analysis demonstrated that the coordination polymers, MnII(dmbpy)[MVN(CN)4] (MV = Mn (1) and Cr (2)), formed a considerably corrugated 2D cyanide-bridged network with a quasi C4v symmetric building unit, [CrVN(CN)4]2-, and trigonal prismatic coordination geometry around MnII. Compound 2 demonstrated a metamagnetic-like ordering at 14.4 K, caused by the intra- and inter-layer antiferromagnetic interactions between CrV (S = 1/2) and MnII (S = 5/2), and a weak ferromagnetic behaviour at 2 K reflecting the single-ion anisotropy of CrV and structural anisotropy.

Delayed surgery for acute type A aortic dissection: a retrospective review of an alternative surgical strategy in the COVID-19 era.

BACKGROUND: During the coronavirus disease (COVID-19) pandemic, medical resources have often been limited to emergency surgeries. This study aimed to evaluate our experience with delayed surgery for acute type A aortic dissections (ATAADs). METHODS: A retrospective study was conducted on 33 patients who underwent surgery for ATAADs between January 2020 and December 2021. The patients were divided into two groups: patients treated within 12 h of arrival (E group; N = 21) and those treated > 12 h after arrival (D group; N = 12) with strict antihypertensive therapy until surgery. RESULTS: The plasma fibrinogen levels on arrival were lower in the D group than in the E group (174.3 ± 109.1 vs 293.4 ± 165.4, p = 0.038). The time to surgery from symptom onset was longer in the D group than in the E group (4 ± 1 h vs. 86 ± 108 h, p < 0.001). There was one case (3%) of mortality and seven cases (21%) of cerebral infarctions in the E group. There was no significant difference in the intraoperative data and quantity of blood transfused between the two groups. CONCLUSION: Thus, delayed surgery for ATAAD with appropriate preoperative management may be an alternative surgical strategy in the COVID-19 era.

Delayed coronary artery stenosis: a rare complication of the left atrial clipping device.

A clipping device may impinge on the coronary artery following left atrial appendage occlusion during cardiac surgery, causing rare cardiac ischaemia perioperatively. This report highlights a case of delayed severe coronary artery stenosis resulting in ventricular fibrillation 2 months after cardiac surgery with the implantation of a left atrial clipping device. Following a percutaneous coronary intervention, the patient underwent clip removal surgery. Postoperative three-dimensional heart model verification revealed that the base of the left atrial appendage was more dorsal than usual, thereby increasing the potential risk of the clip impinging on the coronary artery. We should remember that this rare complication can occur after left atrial clipping, either in the early postoperative period or later.

Visualization of Electrolyte Reaction Field Near the Negative Electrode of a Lead Acid Battery by Means of Amplitude/Frequency Modulation Atomic Force Microscopy.

The precise observation of a solid-liquid interface by means of frequency modulation atomic force microscopy (FM-AFM) was performed, demonstrating its applicability to a study on lead acid batteries using an electrochemical test cell for in-liquid FM-AFM embedded with a specialized cantilever holder. The consistency and reproducibility of each surface profile observed via amplitude modulation AFM and FM-AFM were verified properly in a strong acidic electrolyte. In terms of FM-AFM, the ability to observe remarkable changes in the force mapping is the most beneficial, especially near the negative electrode surface. The localization of lignosulfonate (LS) added into the electrolyte as an expander could be visualized since this characteristic force mapping was captured when LS was added to electrolyte.

Thoracoabdominal aortic aneurysm repair based on pre- and postoperative evaluation of the artery of Adamkiewicz.

OBJECTIVES: The aim of this study was to evaluate our experience with thoraco-abdominal aortic aneurysm repair based on the pre- and postoperative evaluation of the artery of Adamkiewicz (AKA). METHODS: Between April 2017 and May 2021, 32 patients who underwent thoracoabdominal aortic repair underwent pre- and postoperative multidetector row computed tomography (MDCT) for AKA evaluation. Based on the identification of the AKA on preoperative MDCT, only 1 critical segmental artery was reattached to the AKA (CSA-AKA). Postoperative MDCT was used to evaluate the patency of the reattached CSA-AKA. RESULTS: Pre- and postoperative MDCT helped identify and visualize the AKA in all patients (100%). In 8 patients, alternative continuity to the AKA developed through collateral circulation. The total number of CSA-AKA with collateral circulation was 48 among the 32 cases; the number of reattached segmental arteries per case was 1.3 ± 0.9 (range, 0-4). The overall rate of patency of the reattached CSA-AKA was 53% (23/43). Three patients exhibited spinal cord injuries (paraplegia, 2; paraparesis, 1). In the 2 paraplegia cases exhibiting partial or complete occlusion of the reattached CSA-AKA, the development of collateral circulation was not visualized via postoperative MDCT. In the paraparesis case, postoperative MDCT helped visualize the development of collateral circulation to the CSA-AKA, resulting in full recovery at discharge. CONCLUSIONS: The study findings suggest that spinal cord injuries do not occur in the presence of a patent preoperatively identified CSA-AKA or the development of collateral circulation. Pre- and postoperative identification of collateral pathways to the AKA may help reveal paraplegia risk factors.

Laboratory Test Predictors for Major Bleeding in Elderly (≥80 Years) Patients With Nonvalvular Atrial Fibrillation Treated With Edoxaban 15 mg: Sub-Analysis of the ELDERCARE-AF Trial.

Background We investigated the predictors related to major bleeding events during treatment with edoxaban 15 mg in patients aged ≥80 years with nonvalvular atrial fibrillation and high bleeding risk, for whom standard oral anticoagulants are inappropriate, focusing on standard laboratory tests related to bleeding. Methods and Results This was a prespecified subanalysis of the on-treatment analysis set of the ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial. Major bleeding was the primary safety end point. The event rates were calculated according to prespecified characteristics at baseline. A total of 984 Japanese patients were randomly assigned to edoxaban 15 mg or placebo (n=492, each). During the study period, 20 and 11 major bleeding events occurred in the edoxaban and placebo groups, respectively. The adjusted analysis revealed that hemoglobin <12.3 g/dL (adjusted hazard ratio [aHR], 3.57 [95% CI, 1.10-11.55]) and prothrombin time ≥12.7 seconds; (aHR, 2.89 [95% CI, 1.05-8.02]) independently predicted major bleeding, while creatinine clearance <30 mL/min showed a tendency towards an increase in major bleeding (aHR, 2.68; 95% CI, 0.96-7.46). In patients treated with edoxaban lacking these 3 risk factors, no major bleeding occurred; major bleeding event rates increased with each risk factor. Patients with 3 risk factors were significantly more likely to have a major bleeding event at 11.05%/year (HR, 7.15 [95% CI, 1.92-26.71]). Conclusions In elderly patients with nonvalvular atrial fibrillation with high bleeding risk, baseline hemoglobin <12.3 g/dL, prothrombin time ≥12.7 seconds, and creatinine clearance <30 mL/min may predict major bleeding during treatment with edoxaban 15 mg. Registration URL: ELDERCARE-AF https://www.clinicaltrials.gov; Unique number: NCT02801669.