Honeycomb-Layered Oxides With Silver Atom Bilayers and Emergence of Non-Abelian SU(2) Interactions.

Honeycomb-layered oxides with monovalent or divalent, monolayered cationic lattices generally exhibit myriad crystalline features encompassing rich electrochemistry, geometries, and disorders, which particularly places them as attractive material candidates for next-generation energy storage applications. Herein, global honeycomb-layered oxide compositions, Ag2 M2 TeO6 ( M = Ni , Mg , etc $M = \rm Ni, Mg, etc$ .) exhibiting Ag $\rm Ag$ atom bilayers with sub-valent states within Ag-rich crystalline domains of Ag6 M2 TeO6 and Ag $\rm Ag$ -deficient domains of Ag 2 - x Ni 2 TeO 6 ${\rm Ag}_{2 - x}\rm Ni_2TeO_6$ ( 0 < x < 2 $0 < x < 2$ ). The Ag $\rm Ag$ -rich material characterized by aberration-corrected transmission electron microscopy reveals local atomic structural disorders characterized by aperiodic stacking and incoherency in the bilayer arrangement of Ag $\rm Ag$ atoms. Meanwhile, the global material not only displays high ionic conductivity but also manifests oxygen-hole electrochemistry during silver-ion extraction. Within the Ag $\rm Ag$ -rich domains, the bilayered structure, argentophilic interactions therein and the expected Ag $\rm Ag$ sub-valent states ( 1 / 2 + , 2 / 3 + $1/2+, 2/3+$ , etc.) are theoretically understood via spontaneous symmetry breaking of SU(2)× U(1) gauge symmetry interactions amongst 3 degenerate mass-less chiral fermion states, justified by electron occupancy of silver 4 d z 2 $4d_{z^2}$ and 5s orbitals on a bifurcated honeycomb lattice. This implies that bilayered frameworks have research applications that go beyond the confines of energy storage.

Edoxaban versus enoxaparin for the prevention of venous thromboembolism after total knee or hip arthroplasty: pooled analysis of coagulation biomarkers and primary efficacy and safety endpoints from two phase 3 trials.

BACKGROUND: The objective of this analysis was to assess the effects of edoxaban compared with enoxaparin on key coagulation biomarkers and present pooled primary efficacy and safety results from phase 3 STARS E-3 and STARS J-V trials for prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) or total hip arthroplasty (THA). METHODS: In the randomized, double-blind, double-dummy, multicenter, STARS E-3 and STARS J-V trials, patients received edoxaban 30 mg or enoxaparin 2000 IU (20 mg) twice daily for 11 to 14 days. The studies were conducted in Japan and Taiwan; enoxaparin dosing was based on Japanese label recommendations. The primary efficacy endpoint was incidence of VTE; the safety endpoint was major or clinically relevant nonmajor (CRNM) bleeding. Blood samples were taken at presurgical evaluation, pretreatment (postsurgery), predose on day 7, predose on completion of treatment, and at a follow-up examination 25 to 35 days after the last dose of study drug for D-dimer, prothrombin fragment 1 + 2 (F1+2), and soluble fibrin monomer complex (SFMC) measurement. RESULTS: A total of 716 patients enrolled in STARS E-3 and 610 patients enrolled in STARS J-V; 1326 patients overall. This analysis included 657 patients who received edoxaban 30 mg QD and 650 patients who received enoxaparin 20 mg BID. Incidence of VTE was 5.1 and 10.7% for edoxaban and enoxaparin, respectively (P <0.001). Incidence of combined major and CRNM bleeding was 4.6 and 3.7% for edoxaban and enoxaparin, respectively (P = 0.427). On day 7, mean D-dimer (4.4 vs 5.5 µg/mL), F1+2 (363 vs 463 pmol/L), and SFMC (5.7 vs 6.8 µg/mL) were lower in edoxaban-treated patients relative to enoxaparin-treated patients, respectively (P <0.0001 for all). At end of treatment, mean D-dimer (5.4 vs 6.2 µg/mL), F1+2 (292 vs 380 pmol/L), and SFMC (6.2 vs 7.2 µg/mL) were lower in edoxaban-treated patients relative to enoxaparin-treated patients (P <0.0001 for all). CONCLUSIONS: Edoxaban was superior to enoxaparin in prevention of VTE following TKA and THA, with comparable rates of bleeding events. Relative to enoxaparin, edoxaban significantly reduced D-dimer, F1+2, and SFMC. TRIAL REGISTRATION: Clintrials.gov NCT01181102 and NCT01181167. Both registered 8/12/2010.

Clinical benefit of graduated compression stockings for prevention of venous thromboembolism after total knee arthroplasty: post hoc analysis of a phase 3 clinical study of edoxaban.

BACKGROUND: Guidelines from the Japanese Circulation Society recommend prophylaxis with anticoagulation plus intermittent pneumatic compression or graduated compression stockings (GCS) among patients at the highest risk for developing venous thromboembolism (VTE). However, the benefits of concomitant GCS use for patients undergoing total knee arthroplasty (TKA) and receiving anticoagulation remain unknown. In this study, the efficacy of GCS plus anticoagulation compared with anticoagulation alone was evaluated among patients undergoing TKA. METHODS: This study is a post hoc analysis of a previously reported phase 3 trial involving patients undergoing TKA. In the primary study, which permitted the use of GCS for mechanical prophylaxis, patients were randomized to receive edoxaban 30 mg once daily or enoxaparin 20 mg twice daily for 11 to 14 days following TKA. The primary endpoint was the incidence of VTE, a composite of symptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE), and asymptomatic DVT. Treatment comparisons were performed using the chi-square test, and the 95 % confidence intervals were calculated. RESULTS: Among patients receiving edoxaban, the incidence of VTE was 3.8 and 5.8 % for patients with and without GCS, respectively. For patients receiving enoxaparin, VTE incidence was 8.4 and 20.8 % among those with and without GCS, respectively. Overall, VTE incidence was 6.0 and 13.0 % for anticoagulated patients with and without GCS mechanical prophylaxis, respectively. No deaths or symptomatic PE were reported during this study. CONCLUSIONS: Although the incidence of VTE was >2-fold lower among patients receiving anticoagulation plus GCS compared with those receiving anticoagulation alone, statistical significance was not achieved. Further studies are required to confirm the findings of this preliminary analysis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01181102.

Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty: STARS J-V.

BACKGROUND: In the absence of thromboprophylaxis, patients undergoing total hip arthroplasty (THA) are at increased risk for venous thromboembolism (VTE). The objective of this study was to compare the efficacy and safety of edoxaban with enoxaparin for the prevention of VTE after THA in Japan. METHODS: This was a phase 3, double-blind, double-dummy, noninferiority study. Patients undergoing elective, unilateral primary THA were randomized to receive edoxaban 30 mg once daily (n = 307) or enoxaparin 2000 IU (equivalent to 20 mg) twice daily (n = 303) for 11 to 14 days. The primary efficacy endpoint was the incidence of VTE. Safety endpoints included the incidence of major or clinically relevant nonmajor (CRNM) bleeding. RESULTS: The incidence of VTE, based on venography and clinical surveillance, was 2.4 % in the edoxaban group and 6.9 % in the enoxaparin group (P <0.001). The absolute difference in the incidence of VTE was -4.5 % (95 % confidence interval [CI]: -8.6, -0.9), which was within the noninferiority margin set at 8 % for the difference and established the noninferiority of edoxaban to enoxaparin. Since the upper limit of the 95 % CI of the absolute difference was less than 0 %, the superiority of edoxaban over enoxaparin was demonstrated. The incidence of major or CRNM bleeding was 2.6 % in the edoxaban group and 3.7 % in the enoxaparin group (P = 0.475). CONCLUSIONS: Oral edoxaban 30 mg once daily was superior to subcutaneous enoxaparin 2000 IU twice daily in the prevention of VTE following THA without increasing the risk for major or CRNM bleeding.

A randomized, open-label trial of edoxaban in Japanese patients with severe renal impairment undergoing lower-limb orthopedic surgery.

BACKGROUND: Edoxaban is an oral, direct, factor Xa inhibitor approved in Japan for thromboembolic prophylaxis after lower-limb orthopedic surgery (LLOS), but contraindicated in patients with severe renal impairment (SRI; creatinine clearance [CLCR] ≥15 to <30 mL/min). METHODS: This open-label study compared the safety of edoxaban 15 mg once daily in Japanese patients with SRI to that of edoxaban 30 mg in patients with mild renal impairment (MiRI; CLCR ≥50 to ≤80 mL/min; N = 30) undergoing LLOS. Patients with CLCR ≥20 to <30 mL/min were randomized to receive edoxaban 15 mg (N = 22) or subcutaneous fondaparinux 1.5 mg once daily (N = 21). All patients with CLCR ≥15 to <20 mL/min received edoxaban 15 mg (N = 7). Treatment was administered for 11 to 14 days. RESULTS: Major or clinically relevant non-major bleeding occurred in 6.7%, 3.4%, and 5.0% of patients in the MiRI edoxaban 30-mg, SRI edoxaban 15-mg, and SRI fondaparinux groups, respectively; there were no major bleeding events. No thromboembolic events occurred. At all time points assessed, edoxaban plasma concentrations and changes in coagulation biomarkers were similar between the SRI and MiRI groups. CONCLUSIONS: These results suggest edoxaban 15 mg once daily is well tolerated in Japanese patients with SRI undergoing LLOS. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01857583.

Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial.

INTRODUCTION: This phase 3 trial compared the safety and efficacy of edoxaban, an oral direct factor Xa inhibitor, with enoxaparin sodium (enoxaparin) for thromboprophylaxis after total knee arthroplasty (TKA) in patients in Japan and Taiwan. MATERIALS AND METHODS: In this randomized, double-blind, double-dummy study, patients received oral edoxaban 30 mg once daily beginning 6 to 24 hours postsurgery or enoxaparin 2000 IU (equivalent to 20 mg) subcutaneously twice daily beginning 24 to 36 hours postsurgery for 11 to 14 days. The primary efficacy endpoint was the composite of symptomatic pulmonary embolism and symptomatic and asymptomatic deep vein thrombosis. Safety endpoints included the incidence of major bleeding, clinically relevant non-major (CRNM) bleeding, major bleeding or CRNM bleeding, all bleeding events, adverse events, and adverse drug reactions. RESULTS: Of 716 patients enrolled, 360 and 356 were randomized to receive edoxaban or enoxaparin, respectively. The primary efficacy outcome occurred in 22/299 (7.4%) and 41/295 (13.9%) patients in the edoxaban and enoxaparin groups, respectively (relative risk reduction=46.8%), indicating non-inferiority (P <0.001) and superiority (P=0.010) of edoxaban versus enoxaparin. In the edoxaban and enoxaparin groups, major bleeding occurred in 4/354 (1.1%) versus 1/349 (0.3%) patients (P=0.373); major or CRNM bleeding occurred in 22/354 (6.2%) versus 13/349 (3.7%) patients (P=0.129), respectively. CONCLUSIONS: Edoxaban 30 mg once daily was more effective for thromboprophylaxis than subcutaneous enoxaparin 2000 IU twice daily following TKA and demonstrated a similar incidence of bleeding events.

Safety and efficacy of edoxaban in patients undergoing hip fracture surgery.

INTRODUCTION: Edoxaban is an oral, direct, once-daily factor Xa inhibitor. This study evaluated the safety and efficacy of edoxaban compared to subcutaneous enoxaparin in Japanese patients undergoing hip fracture surgery. MATERIALS AND METHODS: In this multicenter, randomized, open-label, active-comparator, phase 3 trial, 92 patients were randomized 2:1 to receive edoxaban 30mg once daily (n=62) or enoxaparin sodium (enoxaparin) 2000IU (equivalent to 20mg) twice daily (n=30) for 11 to 14days. The primary endpoints were the incidence of major or clinically relevant non-major (CRNM) bleeding and incidence of any bleeding events (major, CRNM, or minor bleeding). Secondary efficacy endpoints included the incidence of thromboembolic events, venous thromboembolism-related deaths, and all-cause deaths. Additional adverse events were recorded throughout the study. RESULTS: In the edoxaban and enoxaparin treatment groups, the incidence of major or CRNM bleeding was 3.4% and 6.9%, respectively, while any bleeding event occurred in 25.4% and 17.2% of patients, respectively. The incidence of thromboembolic events was 6.5% in the edoxaban group and 3.7% in the enoxaparin group. All events were asymptomatic deep vein thrombosis. The incidence of adverse events was 72.9% and 82.8% in the edoxaban and enoxaparin groups, respectively. CONCLUSIONS: Compared to subcutaneous enoxaparin 2000IU twice daily, oral edoxaban 30mg once daily demonstrated similar safety and efficacy in the prevention of thromboembolic events in Japanese patients undergoing hip fracture surgery. CLINICAL TRIALS REGISTRATION NUMBER: NCT01181141.

Percutaneous carpal tunnel release compared with mini-open release using ultrasonographic guidance for both techniques.

PURPOSE: To compare the outcomes of percutaneous carpal tunnel release (PCTR) and mini-open carpal tunnel release (mini-OCTR) using ultrasonographic guidance for both techniques. METHODS: We included 74 hands of 65 women with idiopathic carpal tunnel syndrome (age, 52-71 y; mean, 58 y). Thirty-five hands of 29 women had the PCTR (release with a device consisting of an angled blade, guide, and holder, along a line midway between the median nerve and ulnar artery (safe line) under ultrasonography (incision, 4 mm), and 39 hands of 36 women had the mini-OCTR (release along the safe line, distally under direct vision (incision, 1-1.5 cm) and proximally under ultrasonography, using a device consisting of a basket punch and outer tube. RESULTS: Assessments at 3, 6, 13, 26, 52, and 104 weeks showed no significant differences in neurologic recovery between the groups (p > .05). The PCTR group had significantly less pain, greater grip and key-pinch strengths, and better satisfaction scores at 3 and 6 weeks (p < .05), and less scar sensitivity at 3, 6, and 13 weeks (p < .05). There were no complications. CONCLUSIONS: The PCTR provides the same neurologic recovery as does the mini-OCTR. The former leads to less postoperative morbidity and earlier functional return and achievement of satisfaction. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.

Patient education for the treatment of ulnar neuropathy at the elbow.

OBJECTIVE: To assess the effect of patient education, the simplest conservative treatment of ulnar neuropathy at the elbow, and establish its indication. DESIGN: Patients with ulnar neuropathy at the elbow were treated by education. Its effects and factors affecting outcome were investigated. The length of the treatment was at least 3 months. If the symptoms were improving, the follow-up was lengthened. All of the improved patients were followed up at least for 1 year after they reached a plateau of improvement to check recurrence. SETTING: Patients were selected from an outpatient clinic of a general hospital. PARTICIPANTS: Patients (N=77; 80 nerves) with ulnar neuropathy at the elbow diagnosed clinically and electrophysiologically. INTERVENTIONS: Patient education on the pathophysiology and activity modification to unload the ulnar nerve from mechanical stress. MAIN OUTCOME MEASURES: Outcomes were graded as excellent, good, fair, or poor with use of the modified Akahori's classification system. Patient satisfaction was graded as 1 (low) to 5 (high). Repeat nerve conduction studies were performed in those who gave consent, and results were graded as excellent, good, fair, or poor. RESULTS: Fifty-three nerves (66%) had excellent or good outcomes. Multivariate logistic regression analysis revealed that degenerative change (graded as normal, mild, moderate, or severe) was associated with the outcome, while age, sex, side, duration and severity of the disease, diabetes, dislocation of the nerve, and smoking were not. Excellent or good outcomes were obtained in 43 (80%) of 54 nerves with no or mild degeneration and 10 (38%) of 26 nerves with moderate or severe degeneration. Recurrence was less frequent in the former (2 of 43 nerves, 5%) than the latter (4 of 10, 40%). The outcomes strongly correlated with the satisfaction scores and repeat nerve conduction study results. CONCLUSIONS: Patient education is effective for a considerable number of patients with ulnar neuropathy at the elbow. Whether this is indicated depends on the grade of elbow degeneration. Those who have no or mild degeneration respond better to this treatment with a lower rate of recurrence than those with more severe degeneration regardless of age, sex, side, duration and severity of the disease, presence or absence of diabetes and dislocation of the nerve, and smoking status.

Usefulness of arterial blood gas analysis and D-dimer measurement in the assessment of pulmonary embolism after orthopedic surgery.

BACKGROUND: Deep venous thrombosis (DVT) and pulmonary embolism (PE) after spinal or lower extremity surgery are well recognized as common complications. Since 1995 we have investigated the incidence of PE after orthopedic surgery using ventilation-perfusion (V/Q) lung scans, and the prevalence of PE was about 10%. With a view to detecting early-stage PE by simple examinations, we evaluated the use of both the blood gas analysis and the D-dimer measurement after spinal or lower extremity surgery. METHODS: Altogether, 85 patients who underwent spinal or lower extremity surgery were eligible for the study. Pneumatic sequential leg compression devices (PSLCDs) were utilized continuously both intra- and postoperatively. Arterial blood gas analysis and D-dimer measurement were performed pre- and postoperatively on days 3 and 7. We set lung scan criteria as follows: postoperative decrease in Pa(O2) (deltaPa(O2) by > or = 10 torr (group G), postoperative D-dimer of > or = 1 microg/ml (group D), or both. Patients with the criteria went on to undergo lung scans, and PE was diagnosed by the existence of any mismatch between ventilation-perfusion (V/Q) lung scans. RESULTS: A total of 44 (51.8%) patients met the lung scan criteria and underwent perfusion lung scans, 10 (11.7%) of whom were diagnosed as PE. In groups G and D, about 30% showed PE. Moreover, six (85.7%) of the seven patients with both criteria showed a significant increase (83.7%) in the prevalence of PE. CONCLUSIONS: Patients with the above criteria showed a high prevalence of PE. Moreover, 10 (11.7%) of the 85 patients were diagnosed as having PE, which corresponded to the prevalence in our former studies where lung scans were performed in all patients. The blood gas analysis and the D-dimer measurement may be utilized as the first screening examinations.

Use of hydroxy-methyl-glutaryl coenzyme A reductase inhibitors is associated with risk of lymphoid malignancies.

It has been speculated that the use of hydroxy-methyl-glutaryl coenzyme A reductase inhibitors (statins) is associated with the risk of malignant diseases. Considering their immunosuppressive activities, malignant diseases that are associated with an immunosuppressive status seem feasible to examine the association. We therefore examined the association between statin use and development of lymphoid malignancies in a case-control study. Cases were 221 consecutive incident cases with histopathologically proven lymphoid malignancies (lymphoma and myeloma), hospitalized in the Department of Hematology of Toranomon Hospital (Tokyo, Japan) between 1995 and 2001. Two independent control groups, comprising 442 and 437 inpatients without malignancies from the Departments of Orthopedics and Otorhinolaryngology of the same hospital, were selected to test for consistency of association. Controls were matched individually with cases for age, sex and year of admission. Subject information, including statin use, was abstracted from medical records at the time of hospitalization. Strength of association was evaluated as an adjusted odds ratios (aOR) using a conditional logistic regression model. A higher frequency of statin use was found among patients with lymphoid malignancies in comparison with both orthopedic (aOR 2.11, 95% CI 1.20-3.69, P = 0.009) and otorhinolaryngology patients (aOR 2.59, 95% CI 1.45-4.65, P = 0.001), the significance being maintained when the two control groups were combined (aOR 2.24, 95% CI 1.37-3.66, P = 0.001). In conclusion, we observed an elevated risk of lymphoid malignancy with statin use among Japanese patients. Further evaluations in different populations are required to draw conclusions as to the carcinogenicity of lymphoid malignancies with statin use.

Hypercholesterolemia as a risk factor for idiopathic carpal tunnel syndrome.

In idiopathic carpal tunnel syndrome (CTS), the median nerve is enlarged within the carpal tunnel due to intraneural connective tissue proliferation. Because hypercholesterolemia, especially increase in low-density lipoprotein (LDL), has been associated with fibrogenesis, we investigated the association of median nerve cross-sectional area and prevalence of idiopathic CTS with serum lipid measurements in middle-aged patients and controls. We found that nerve area and prevalence of CTS were correlated with serum LDL levels. Thus, high LDL levels in middle age are a risk factor for idiopathic CTS, suggesting that the LDL-correlated median nerve enlargement increases the volume of the carpal tunnel contents.

Ultrasonographic measurement of median nerve cross-sectional area in idiopathic carpal tunnel syndrome: Diagnostic accuracy.

Severity-correlated enlargement of the median nerve occurs in idiopathic carpal tunnel syndrome (CTS). We determined whether measurement of the nerve cross-sectional area was useful in making the diagnosis of CTS. In 414 wrists of 275 patients with clinically diagnosed idiopathic CTS and 408 wrists of 408 controls, we made ultrasonographic measurements of the nerve area at the distal (distal edge of the flexor retinaculum), mid (hook of the hamate), and proximal carpal tunnel (wrist crease). Criteria based on the area at a single level yielded sensitivities of 43-57% and specificities of 96-97%. Use of the mean carpal nerve area (average of the areas at the three levels) improved the results (sensitivity, 67%; specificity, 97%), which was as sensitive as the nerve conduction studies (NCS). In the NCS, we obtained sensitivities of 66% for the distal motor nerve latency and 67% for the distal sensory nerve latency, with specificities of 97% for each. A combination of the mean carpal nerve area and NCS criteria yielded a sensitivity of 84% and a specificity of 94%. The clinical implications of these findings for the diagnosis of CTS are discussed.