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Objectives Patients with rheumatoid arthritis (RA) usually switch to a second biological disease-modifying antirheumatic drugs (bDMARDs) when the first has proven to be ineffective, although some may discontinue bDMARDs treatment altogether. We investigated the total rate of bDMARDs retention and the risk of bDMARDs discontinuation in patients with RA. Methods The study included 564 patients with RA who started bDMARDs treatment before 2008 ( Results Among 564 patients, 74 had discontinued bDMARDs treatment due to AEs. Male sex and Steinbrocker class 3–4 were more frequent, while rheumatoid factor and concomitant methotrexate treatment were less frequent, in those aged ≥65 years than in those aged Conclusions Older patients are at higher risk of discontinuing bDMARDs treatment due to AEs than younger patients.

SONIALVISION G4 (Shimadzu, Kyoto, Japan) is a fluoroscopic imaging system capable of dual-energy X-ray absorptiometry (DXA) using the additional application. However, bone mineral density (BMD) with this system is calibrated only by a phantom, and the necessity to confirm the reliability of BMD measurement in human subjects has been pointed out. This study aimed to evaluate the clinical reliability of BMD measurement using SONIALVISION G4 by comparing it with PRODIGY (GE Healthcare, Madison, WI, USA), a reference system in developing the DXA application. BMD measurements using these two DXA systems were performed on the same day at the lumbar spine and bilateral proximal femur of 130 subjects aged 22–86 years. The agreement and correlation between the measurements were determined. Thirty out of the 130 subjects were scanned twice to determine the precision of the SONIALVISION G4 system. BMD was highly correlated between the two DXA systems both at the lumbar spine and proximal femur, with correlation coefficients ranging from 0.963 (left total hip) to 0.989 (left femoral neck). Differences in BMD measured by the two systems were less than 3.0%, but a small proportional bias was observed in the Bland–Altman analysis. Coefficients of variation in BMD measurement were 1.77% in the lumbar spine and 1.41–2.76% in the proximal femur. Although BMD values by SONIALVISION G4 were close to those by PRODIGY, follow-up studies should be performed using the same device because of the small difference between devices.

Glucocorticoids are important drugs used to treat rheumatoid arthritis. We recommend glucocorticoid discontinuation as soon as possible given the associated side-effects, but many patients continue to take oral glucocorticoids long-term. The present study aimed to explore factors associated with glucocorticoid discontinuation at 52 weeks after initiating biological disease-modifying antirheumatic drugs (bDMARDs). Subjects were 564 patients from a Japanese multicenter registry who were administered glucocorticoids and methotrexate (MTX) followed by initiation of the first bDMARD. We examined the status of oral glucocorticoid use at 52 weeks after initiating the first bDMARD. By 52 weeks after bDMARD initiation, 164 patients (29.1%) discontinued glucocorticoids. Multivariable analysis identified age, MTX dose, and glucocorticoid dose as factors independently associated with glucocorticoid discontinuation. After adjusting for baseline characteristics using propensity score matching, among patient groups administered MTX ≤ 8 mg/week and MTX > 8 mg/week, 105 pairs remained. A significantly higher rate of glucocorticoid discontinuation (41.0%) was noted for patients administered MTX > 8 mg/week. Our findings suggest that glucocorticoids may be discontinued after initiating bDMARDs. Moreover, higher MTX doses (>8 mg/week) at the time of bDMARD initiation were associated with glucocorticoid discontinuation among patients treated with bDMARDs.

[Purpose] Few previous studies have delimitated the palpation zone of the gluteus medius muscle with a focus on its fiber bundles. The purpose of this study was to clarify the morphological characteristics of the gluteus medius muscle using an anatomical approach, and to define its proper palpation zone. [Participants and Methods] In this study, we evaluated thirteen halves of the pelvic region in seven formalin-fixed cadavers. We identified the borders between the iliotibial band and gluteus medius muscle, and between the gluteus medius and gluteus maximus muscles, on the iliac crest. Furthermore, we quantified the border points of the gluteus medius' fiber bundles and observed its anatomical and morphological characteristics. [Results] We identified two fiber bundles in the gluteus medius muscle, an anterior and a posterior fiber bundle, and detected that a portion of the posterior fibers was located subcutaneously. [Conclusion] We propose that the region where the posterior fibers of the gluteus medius muscle are located subcutaneously is an appropriate zone for the palpation of this muscle.

Protamine causes cardiac depression, which may be mediated by tumor necrosis factor alpha (TNF-α). Ulinastatin, a human urinary protease inhibitor, inhibits TNF-α. Here, we aimed to investigate whether ulinastatin prevented protamine-induced myocardial depression by inhibiting TNF-α. Rat hearts were perfused using a Langendorff system, and three protocols were followed. Protocol 1: The hearts were divided into saline, ulinastatin-low, and ulinastatin-high groups. Protamine was administered to each group, and myocardial contractility was the primary outcome. Protocol 2: The hearts were allotted to saline or ulinastatin group. Protamine was administered to each group. TNF-α expression in the coronary effluent and myocardial tissue was measured. Protocol 3: The hearts were allotted to saline and ulinastatin groups. Recombinant rat-TNF-α was administered to each group. Protamine alone reduced the maximum left ventricular pressure derivative (LV dP/dt max) by 45 ± 4%. In contrast, the reduction in LV dP/dt max was 4 ± 3% in the ulinastatin-high group. Compared with that in the saline group, the increase in TNF-α in the coronary effluent was attenuated in the ulinastatin group. Recombinant TNF-α alone reduced LV dP/dt max (- 21 ± 14%). In contrast, when TNF-α was added in the presence of ulinastatin, the decrease in LV dP/dt max was prevented significantly (- 3 ± 8%). We showed, for the first time, that ulinastatin protected against protamine-induced myocardial damage, both by inhibiting TNF-α synthesis and by directly preventing the cardiodepressant action of TNF-α.

Insulin exerts positive inotropic effects on cardiac muscle; however, the relationship between cardiac contractility and phosphoinositol-3-kinase/Akt (PI3K/Akt) activation remains unclear. We hypothesized that the positive inotropic effects of insulin are dose-dependent and mediated via the PI3K/Akt pathway in isolated normal rat hearts. The Institutional Animal Investigation Committee approved the use of hearts excised from rats under pentobarbital anesthesia. The hearts were perfused at a constant pressure using the Langendorff technique. After stabilization (baseline), the hearts were randomly divided into the following four insulin (Ins) groups: 1) Ins0 (0 IU/L), 2) Ins0.5 (0.5 IU/L), 3) Ins5 (5 IU/L), and 4) Ins50 (50 IU/L) (n = 8 in each group). To clarify the role of the PI3K/Akt pathway in insulin-dependent inotropic effects, we also treated the insulin groups with the PI3K inhibitor wortmannin (InsW): 5) InsW0 (0 IU/L), 6) InsW0.5 (0.5 IU/L), 7) InsW5 (5 IU/L), and 8) InsW50 (50 IU/L). Hearts were perfused with Krebs–Henseleit buffer solution with or without wortmannin for 10 min, followed by 20 min perfusion with the solution containing each concentration of insulin. The data were recorded as the maximum left ventricular derivative of pressure development (LV dP/dt max). Myocardial p-Akt levels were measured at 3 min, 5 min, and at the end of the perfusion. In the Ins groups, LV dP/dt max in Ins5 and Ins50 increased by 14% and 48%, respectively, 3 min after insulin perfusion compared with the baseline. Tachyphylaxis was observed after 10 min in the Ins5 and Ins50 treatment groups. Wortmannin partially inhibited the positive inotropic effect of insulin; although insulin enhanced p-Akt levels at all time points compared with the control group, this increase was suppressed in the presence of wortmannin. The positive inotropic effect of insulin is dose-dependent and consistent with Akt activation. This effect mediated by high doses of insulin on cardiac tissue was temporary and caused tachyphylaxis, potentially triggered by Akt overactivation, which leads beta 1 deactivation.

Objectives The study aimed to investigate the effectiveness and tolerance of biological disease-modifying antirheumatic drugs (bDMARDs) therapy administered concomitantly with tacrolimus (TAC) treatment in patients with rheumatoid arthritis. Methods 2792 patients who underwent therapy with five bDMARDs (etanercept: ETN, adalimumab, golimumab, tocilizumab, and abatacept: ABT) were enrolled. Among the study subjects, 1582 were concomitant methotrexate (MTX group), 147 were concomitant TAC (TAC group), and 1063 were non-concomitant MTX and TAC (non-MTX/TAC group). The primary outcome was the incident rate of discontinuation of bDMARDs by adverse events (AEs) or loss of efficacy. Results Concerning the analysis for each reasons of discontinuation, including AEs and loss of efficacy, the hazards ratio (HR) was significantly lower in the TAC group than in non-MTX/TAC groups (AEs: HR = 0.39, 95% confidence interval, 0.23–0.68, loss of efficacy: HR = 0.49, 95% confidence interval, 0.30–0.78). The loss of efficacy with the use of ETN and ABT was lower in the TAC group than in non-MTX/TAC groups. Concomitant TAC did not induce elevated risk for discontinuation of AEs in all bDMARD analyses. Conclusions Concomitant TAC with ABT or ETN showed higher retention rates than bDMARDs therapy without TAC or MTX. AEs did not increase over long-term observation.

Background: Lactoferrin, an iron-binding glycoprotein, is known to have protective effects against intestinal and cerebral ischemia-reperfusion (IR) injuries; however, its cardioprotective effects against the stunned myocardium are unknown. This study aimed to test the hypothesis that lactoferrin has cardioprotective effects against stunned myocardium. Methods: Using isolated rat hearts (Langendorff system), we determined the effects of lactoferrin administered enterally and by direct cardiac perfusion. Rat hearts were perfused using the Langendorff system, and two experiments were performed. In experiment 1, the hearts were divided into the enteral lactoferrin (E-LF) 7.5 m, 15 m, 30 m, and 60 m groups, where lactoferrin (1000 mg/kg) was administered enterally 7.5, 15, 30, and 60 min, respectively, before perfusion; and a control group, where saline was administered 30 min before perfusion. In experiment 2, hearts were allocated to the perfusate lactoferrin (P-LF) 15 and 100 groups, where 15 mg/L and 100 mg/L lactoferrin were respectively added to the perfusate, and a control group. Each group was perfused for 20 min prior to 15 min of no-flow ischemia with pacing, followed by 20 min of reperfusion. The primary outcome was the maximum left ventricular derivative of pressure development (LV dP/dt max) 15 min after reperfusion. Myocardial phospho-protein kinase B (p-Akt) was assayed using western blotting. Results: The LV dP/dt max 15 min after reperfusion in the E-LF 15 and 30 m groups was significantly higher than that in the control group. However, the effects disappeared in the E-LF 60 m group. In the second experiment, there were no significant differences in LV dP/dt max. Myocardial p-Akt was not significantly activated in any lactoferrin group. Conclusion: Cardioprotection was observed 15–30 min after enteral lactoferrin but not by direct cardiac perfusion with lactoferrin. Myocardial p-Akt was not associated with the cardioprotective effect. The cardioprotective effect may be induced by enteral lactoferrin-induced substances.

Several efforts have been made to use virtual reality (VR) and augmented reality (AR) for medical and dental education and surgical support. The current methods still require users to wear devices such as a head-mounted display (HMD) and smart glasses, which pose challenges in hygiene management and long-term use. Additionally, it is necessary to measure the user’s inter-pupillary distance and to reflect it in the device settings each time to accurately display 3D images. This setting is difficult for daily use. We developed and implemented a novel anatomy education method using a spatial reality display capable of stereoscopic viewing with the naked eye without an HMD or smart glasses. In this study, we developed two new applications: (1) a head and neck anatomy education application, which can display 3D-CG models of the skeleton and blood vessels of the head and neck region using 3D human body data available free of charge from public research institutes, and (2) a DICOM image autostereoscopic viewer, which can automatically convert 2D CT/MRI/CBCT image data into 3D-CG models. In total, 104 students at the School of Dentistry experienced and evaluated the system, and the results suggest its usefulness. A stereoscopic display without a head-mounted display is highly useful and promising for anatomy education.

BackgroundThis study compared hand function and the cost effectiveness of treatment between collagenase Clostridium histolyticum (CCH) injection and limited fasciectomy for patients with Dupuytren’s contracture (DC).Materials and MethodsThe CeCORD-J study is a prospective, multicenter, non-randomized controlled, observational study of two parallel groups. Participants were DC patients with multiple affected fingers, including flexion contracture of the proximal interphalangeal (PIP) joint. The primary outcome was the Hand10 score, as a patient-reported outcome measure. We set secondary outcomes of EQ-5D-5L score, degree of extension deficit, and direct cost. Propensity score adjustment was used to balance differences in patient characteristics between groups.ResultsParticipants comprised 52 patients in the Collagenase group and 26 patients in the Surgery group. Hand10 score was significantly better in the Collagenase group at 1 and 2 weeks. EQ-5D-5L score was significantly higher in the Collagenase group at 8 weeks. Mean direct cost was 248,000 yen higher in the Surgery group than in the Collagenase group. Extension deficit angle of the PIP joint was significantly larger in the Collagenase group at 26 weeks.ConclusionsCCH injection provides better short-term hand function and cost effectiveness than surgery.UMIN-CTR (UMIN000029826)

Objective Abatacept (ABT) demonstrates good clinical efficacy and retention in rheumatoid arthritis (RA) patients. However, no rescue treatment option against inadequate response to ABT exists. Since tacrolimus (TAC) and ABT suppress T lymphocytes via different mechanisms and a combination of these agents could potentially be effective, this study aimed to examine the efficacy and safety of add-on TAC therapy in RA patients with inadequate response to ABT. Methods Of 550 patients treated with ABT and registered in a Japanese multicenter registry, 25 consecutive patients who underwent add-on TAC therapy and were followed for longer than 24 weeks were included in this study. Results Mean patient age was 67.0 years, disease duration was 16.2 years, and duration of ABT treatment was 1.2 years at the initiation of add-on TAC therapy. Mean TAC dose was 1.2 mg/d at baseline and 1.6 mg/d at week 24. Mean Disease Activity Score of 28 joints - erythrocyte sedimentation rate was significantly improved at week 24 (3.35) relative to baseline (4.97). The proportion of patients who achieved low disease activity or remission was 40.0%, and the European League Against Rheumatism moderate or good response was 72.0%. ABT retention rate was 92.0% at week 24, as calculated by Kaplan-Meier analysis. Only one patient discontinued add-on TAC therapy due to an adverse event (itching sensation). Conclusion This is the first report describing the efficacy and safety profile of add-on TAC therapy with a focus on RA patients with inadequate response to ABT. Our findings suggest that add-on TAC therapy is a worthwhile complementary treatment option in daily clinical practice.

Discontinuation of biologic therapy in rheumatoid arthritis is attributable to various reasons, with the most important cause being insufficient response. In this study, we investigated the association between rheumatoid factor (RF) and anti-citrullinated protein autoantibody (ACPA) status and the discontinuation of tumor necrosis factor inhibitors (TNFi) therapy due to insufficient response in bio-naïve rheumatoid arthritis (RA) patients.This study included patients enrolled in the Tsurumai Biologic Communication Registry in Japan. The crude comparison of TNFi discontinuation due to ineffectiveness between seropositive and seronegative patients was analyzed using the cumulative incidence function of competing events and Gray test. We assessed the associations between baseline patient characteristics and discontinuation of TNFi therapy due to insufficient response using Fine-Gray proportional hazard regression. Fine-Gray proportional hazard analysis considered competing events of interest, including insufficient response, adverse event, palliation, and personal reasons.Of 1237 patients evaluated, 79.3% were positive for RF and 85.4% for ACPA; 72.6% were double positive and 11.1% were double negative. TNFi therapy had been discontinued because of insufficient response at 200 weeks in 19.8% RF-positive, 16.7% RF-negative, 23.0% ACPA-positive, and 13.8% ACPA-negative patients. There was a significantly higher discontinuation rate due to insufficient response in ACPA-positive patients than in ACPA-negative patients using Gray test, with a similar trend as that for RF status. RF positivity was significantly predictive of the discontinuation of TNFi therapy due to ineffectiveness using Fine-Gray proportional hazard regression analysis after adjusting for baseline characteristics, including age, sex, stage, class, disease activity at baseline, methotrexate use, and prednisolone use [hazard ratio 1.73 (95% confidence interval 1.07-2.80)].Using Fine-Gray proportional hazard regression, we demonstrated that RF positivity was related to a higher discontinuation rate of TNFi therapy due to ineffectiveness in bio-naïve RA patients. Key Points • RF positivity is related to a higher discontinuation rate of TNFi therapy due to ineffectiveness. • ACPA is not predictive of a discontinuation of TNFi therapy due to ineffectiveness.

To compare the clinical outcomes of abatacept between rheumatoid arthritis patients with and without concomitant methotrexate (MTX) treatment in daily clinical practice. A retrospective cohort study was performed using data from a multicentre registry. A total of 176 consecutive rheumatoid arthritis patients treated with abatacept were included. The propensity score based on multiple baseline characteristic variables was calculated, and 41 of 86 patients treated without MTX (MTX(−)) and 41 of 90 patients treated with concomitant MTX (MTX(+)) were statistically extracted and analysed. Clinical outcomes were evaluated and compared between the two groups over a 52-week period. Baseline characteristics were statistically comparable. No significant differences were observed in the following clinical outcomes from baseline throughout the 52-week period: drug retention rate (MTX(−)/MTX(+) 79.1%/80.5%), mean change in disease activity score based on 28 joints (DAS28-CRP) from baseline (− 1.35/− 1.54), low disease activity rate (48.8%/43.9%), clinical remission rate (31.7%/36.6%), moderate European League Against Rheumatism (EULAR) response rate (68.3%/68.3%), and good EULAR response rate (36.6%/41.1%) at 52 weeks. In rheumatoid arthritis patients with similar background characteristics undergoing abatacept treatment, concomitant MTX does not seem to affect clinical outcomes. Abatacept would be a suitable treatment option in daily clinical practice in patients with contraindications to MTX. • This is the first study to directly compare the clinical efficacy and safety of abatacept between patients with and without concomitant methotrexate (MTX) treatment in ‘real-world’ settings using the propensity score matching method. • There were no significant differences in clinical outcomes of abatacept between patients with and without concomitant MTX treatment. • We used data from a large Japanese multicentre registry for biologics in rheumatoid arthritis, thereby decreasing selection bias based on the personal preferences of physicians.

Background While lactoferrin, an iron-binding glycoprotein, has protective effects on intestinal and cerebral ischemia-reperfusion injuries, its cardioprotective effects against stunned myocardium are unknown. This study aimed to test the hypothesis that lactoferrin has cardioprotective effects against stunned myocardium. Methods Rat hearts were perfused using the Langendorff system, and two experiments were performed. In experiment 1, the hearts were divided into the enteral lactoferrin (E-LF) 7.5 m, 15 m, 30 m, and 60 m groups, where lactoferrin (1000 mg/kg) was administered enterally for 7.5, 15, 30, and 60 min, respectively, before perfusion; and a control group, where saline was administered 30 min before perfusion. In experiment 2, hearts were allocated to the perfusate lactoferrin (P-LF) 15 and 100 groups, where 15 mg/L and 100 mg/L lactoferrin were respectively added to the perfusate, and a control group. Each group was perfused for 20 min prior to 15 min of no-flow ischemia with pacing, followed by 20 min of reperfusion. The primary outcome was the maximum left ventricular derivative of pressure development (LV dP/dt max) 15 min after reperfusion. Myocardial phospho-protein kinase B (p-Akt) was assayed by western blotting. Results LV dP/dt max in the E-LF 15 m and 30 m groups was significantly higher than in the control group. In the second experiment, there were no significant differences in LV dP/dt max. Myocardial p-Akt was not significantly activated in any lactoferrin group. Conclusion Cardio-protection was observed with enteral but not parenteral lactoferrin administration, and myocardial p-Akt was not involved in this effect.

This study aimed to evaluate the effectiveness of abatacept (ABA) by anti-cyclic citrullinated peptide (ACPA) status on disease activity as well as radiographic progression in patients with rheumatoid arthritis (RA) in clinical settings. A retrospective cohort study was conducted using data from a multicenter registry. Data from a total of 553 consecutive RA patients treated with intravenous ABA were included. We primarily compared the status of disease activity (SDAI) and radiographic progression (van der Heijde modified total Sharp score: mTSS) between the ACPA-negative (N = 107) and ACPA-positive (N = 446) groups. ‘ACPA positive’ was defined as ≥ 13.5 U/mL of anti-CCP antibody. Baseline characteristics between groups were similar. The proportion of patients who achieved low disease activity (LDA; SDAI ≤ 11) at 52 weeks was significantly higher in the ACPA-positive group. Multivariate logistic regression analysis identified ACPA positivity as an independent predictor for achievement of LDA at 52 weeks. Drug retention rate at 52 weeks estimated by the Kaplan–Meier curve was significantly higher in the ACPA-positive group. Achievement rate of structural remission (ΔmTSS ≤ 0.5) at 52 weeks was similar between groups. ABA treatment demonstrated a significantly higher clinical response and higher drug retention rate in ACPA-positive patients. Progression of joint destruction was similar between the ACPA-negative and ACPA-positive groups. Close attention should be paid to joint destruction even in patients showing a favorable response to ABA, especially when the ACPA status is positive.

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with irreversible joint destruction. Severe large joint destruction causes functional disability and pain, requiring total joi...

This study aimed to determine whether serum matrix metalloproteinase-3 (MMP-3) levels can predict remission in rheumatoid arthritis (RA) patients treated with adalimumab (ADA).Subjects were 114 RA patients continuously treated with ADA for 52 weeks. Predictive factors at baseline and 4 weeks after initiation of ADA therapy for the achievement of remission (28-point count Disease Activity Score-CRP (DAS28-CRP) 2.3) at 52 weeks were evaluated by multivariate logistic regression analysis.DAS28-CRP at 4 weeks (odds ratio (OR) 0.614, 95% confidence interval (CI) 0.382-0.988) and improvement in serum MMP-3 levels at 4 weeks (OR 1.057, 95% CI 1.002-1.032) were independent predictors of remission at 52 weeks. The best cut-off level of DAS28-CRP and improvement in serum MMP-3 levels at 4 weeks for predicting remission at 52 weeks was 3.73 (sensitivity: 90%, specificity: 50%, area under the receiver operating characteristic curve (AUC): 62%) and 39.93% (sensitivity: 47%, specificity: 83%, AUC: 64%), respectively.Our findings suggest that a high rate of improvement in serum MMP-3 levels at 4 weeks after initiation of ADA therapy can predict remission at 52 weeks in RA patients.

Background While acute hyperglycemia has been shown to mitigate the beneficial effects of ischemic preconditioning, its effect on insulin-induced preconditioning remains unclear. Methods The study was designed to test the hypothesis that acute hyperglycemia diminishes the cardioprotective effects following a 20-min pre-ischemic pre-conditioning with insulin in the isolated rat heart using the Langendorff system. Forty hearts were assigned to receive modified Krebs–Henseleit (KH) buffer containing 0.5 U/L insulin and 100 mg/dL glucose (InsG100, n = 10), KH buffer with 100 mg/dL glucose (G100, n = 10), KH buffer supplemented with 0.5 U/L insulin and 600 mg/dL glucose (InsG600, n = 10), or with 600 mg/dL glucose (G600, n = 10). To match the osmotic pressure of the InsG600 group, 27.5 mmol/L of mannitol was added to KH solution in the InsG100 and G100 group. The four groups were perfused with each solution for 20 min prior to 15 min of no-flow ischemia, and during 20 min of reperfusion. Only during the ischemic period the heart was paced at 222 beats/min. Measurements of heart rate, coronary flow and maximum of LV derivative of pressure development (dP/dt max) were recorded. Myocardial phospho-protein kinase B (p-Akt) and tumor necrosis factor-α (TNF-α) levels were assayed by enzyme-linked immunosorbent assay and sandwich ELISA, respectively following reperfusion. Results After reperfusion, LV dP/dt max and heart rate in the InsG100 group was significantly higher than that in the other three groups. The myocardial p-Akt level in the InsG100 group was significantly elevated when compared to the InsG600 group at the end of reperfusion. The p-Akt levels in the InsG600 and InsG100 group were significantly higher than in the corresponding non-insulin groups. Conclusions Acute hyperglycemia diminishes the cardioprotective effects of insulin preconditioning in the isolated rat heart, possibly mediated through the suppression of myocardial Akt phosphorylation.

A 62-year-old male patient suddenly developed severe dyspnea due to bilateral vocal cord paralysis (VCP) 4 days after an abdominal surgery. Emergent tracheostomy effectively improved the patient's respiratory status. The present case report emphasizes that bilateral VCP could occur even several days after an abdominal surgery in patients with multiple risk factors, such as hypertension, diabetes mellitus, an older age, male sex, and an upper abdominal surgery. Even if the patient does not present with hoarseness, bilateral VCP should not be ruled out, because a slight phonetic change can be the only symptom of early-stage bilateral VCP.

To explore predictive factors including MMP-3 for achievement of low disease activity (LDA) at 52 weeks in bio-switch rheumatoid arthritis (RA) patients treated with abatacept, for whom obtaining a good clinical response can be difficult.Participants were 423 consecutive patients with RA treated with abatacept who were observed for longer than 52 weeks and registered in the TBCR, a Japanese multicentre registry system. Multivariate logistic regression analysis was used to study factors that predict the achievement of LDA at 52 weeks in bio-naïve (n=234) and bio-switch (n=189) groups.ROC analysis revealed that MMP-3 improvement rates at 12 weeks in bio-switch patients had the highest AUC with a cut-off value of 20.0% for predicting LDA achievement at 52 weeks. Multivariate logistic regression analysis revealed that, in addition to DAS28-CRP at baseline, achieving 20% improvement in MMP-3 levels at 12 weeks was an independent predictive factor (adjusted OR: 4.277, p=0.003) in the bio-switch group, whereas DAS28 was the only predictor in the bio-naïve group. Patients who achieved 20% improvement in MMP-3 levels at 12 weeks had significantly higher achievement rates of LDA at 52 weeks compared to those who did not achieve 20% improvement in the bio-switch group (60.0 vs. 33.3%, p=0.001).Our findings suggest that improvement in MMP-3 levels is key to predicting the clinical efficacy of abatacept. Closer attention paid not only to major clinical indices, but also changes in MMP-3 levels, could improve our ability to optimise clinical results when treating bio-switch patients.

This study investigated displacement of the tracheal tube caused by different methods of intubating stylet removal, using in-vitro experiments and mathematical analysis. In the first in-vitro experiment, we measured the distance travelled by the tube tip during stylet extraction. Then, we investigated the ideal technique for stylet extraction using mathematical analysis, which would cause minimal tube displacement. Then, using a training manikin, we measured the force applied to the vocal cords and stylet extraction force during tracheal intubation. When the stylet was extracted along a straight path towards the stylet end, the distance travelled by the tube tip significantly increased as the bending angle increased. Mathematical analysis revealed that the stylet should be diagonally extracted (in the sagittal plane) at an appropriate angle, rather than along a straight path towards the direction of the stylet end. In simulated tracheal intubation, extraction force and force applied to the vocal cords both significantly increased as the bending angle increased. Compared with the 'hockey stick'-shaped stylet, the arcuate-shaped stylet resulted in reduced force. Our results indicate the potential risk for vocal cord injury when using hockey stick-shaped stylets with large bending angles.

Objective.To evaluate the rates of retention and discontinuation of adalimumab (ADA) due to efficacy and safety in Japanese patients with rheumatoid arthritis (RA).Methods.All patients with RA (n = 476) who were treated with ADA in the Tsurumai Biologics Communication Registry were enrolled.Results.The retention rate of ADA was 46% at 5 years. When focusing on insufficient efficacy, previous biologics use and high baseline disease activity were significant risk factors for up to 1 year. Methotrexate (MTX) use was a significantly low risk factor after 1 year of treatment.Conclusion.Concomitant MTX contributes to the longterm efficacy of ADA therapy.

This study aimed to identify predictive factors for achieving low disease activity (LDA) in rheumatoid arthritis (RA) patients switching from tumor necrosis factor inhibitors (TNFis) to abatacept (ABT). Patients who were registered in the multicenter observational Tsurumai Biologics Communication Registry (TBCR) were enrolled in this study. Predictive factors for LDA achievement at each time point were determined by univariate and multivariate logistic regression analyses. The cutoffs of 28-point count Disease Activity Score (DAS28)-C-reactive protein (CRP) and ΔDAS28-CRP from baseline up to 24 weeks for LDA achievement at 52 weeks were explored using receiver operating characteristic (ROC) curves. Of 2771 RA patients registered until 2013, 76 with moderate or high disease activity were selected. Twenty-six percent of the patients achieved LDA. Multivariate analysis confirmed that DAS28-CRP at 12 weeks and ΔDAS28-CRP from baseline to 12 weeks were independent factors for LDA achievement at 52 weeks [odds ratio (OR) 0.26, 95% confident interval (CI) (0.12-0.56), OR 0.25, 95% CI (0.11-0.57), respectively]. The best cutoff values of DAS28-CRP at 12 weeks and ΔDAS28-CRP from baseline to 12 weeks for LDA at 52 weeks were 3.9 (sensitivity 0.85, specificity 0.78) and -0.97 (sensitivity 0.70, specificity 0.70), respectively. Seventy-one percent of patients who achieved both of these cutoff values at 12 weeks achieved LDA at 52 weeks. Our findings suggest that the clinical course up to 12 weeks is important for predicting long-term outcomes when switching from TNFis to ABT.

We report the successful anesthetic management of Hardy's operation in a patient with acromegalic heart failure. A 43-year-old man, weighing 98 kg, 182 cm in height, was scheduled for Hardy's operation under general anesthesia. He was admitted 'to our hospital with acute heart failure. At admission, the left ventric- ular ejection fraction (EF) decreased to 20% ; however, the angiography revealed no evidence of coronary artery stenosis. His physical features (enlargement of hand, feet, lips and ears, expansion of the skull at the fontanel) and a high level of growth hormone indicated acromegaly. Thus, we concluded that heart failure was due to acromegaly (acromegaly cardiomyopathy : AHD). The patient was scheduled for Hardy's opera- tion. Anesthesia was induced with midazolam, fentanyl, ketamine, propofol and rocuronium, and maintained with desflurane, remifentanil and intermittent doses of fentanyl. We used FlotracTM/VigileoTM monitor(Edwards Lifesciences) to check cardiac output and stroke vol- ume variation during operation. Intraoperative and postoperative hemodynamic variables remained stable. At follow-up 6 months after operation, he was clinically stable with no recurrence of heart failure, and repeat echocardiography demonstrated resolution of the myo- cardial dysfunction (EF 50%). Although acromegaly is well known as being associated with difficult laryngos- copy and intubation, we should pay attention to the presence of acromegalic heart disease. Improvement of cardiac function is expected after surgical therapy.

Objective: To study the clinical effectiveness and long-term retention rate of abatacept (ABA) in elderly rheumatoid arthritis (RA) patients in daily clinical practice.Methods: A retrospective cohort study was performed using data from a multicenter registry. Our study population comprised 500 consecutive RA patients treated with ABA. We compared clinical effectiveness and ABA retention rates between the Young (≤62 years), Middle (62 to 72 years), and Elderly (≥72 years) groups. We also performed separate examinations to identify predictive factors for ABA discontinuation in those with versus those without concomitant methotrexate (MTX) treatment.Results: Mean age was 52.7 years in the Young group, 67.7 years in the Middle group, and 78.1 years in the Elderly group. No significant group-dependent differences were found in mean DAS28 score, categorical distribution of DAS28, and EULAR response rate across the 52 weeks. The ABA retention rates at three years as determined by the Kaplan-Meier method were similar in all three groups. Patient age was not a significant predictor of ABA discontinuation due to adverse events in patients with concomitant MTX; however, it was found to be a significant predictor for those who did not use MTX (Cox hazard model).Conclusion: ABA would be a reasonable treatment option for elderly RA patients from the viewpoints of both clinical effectiveness and long-term retention. However, physicians should watch carefully for any serious adverse reactions in elderly RA patients with intolerance to MTX.

In a student course of gross anatomy dissection at Kanagawa Dental University in 2011, we encountered anomalous case of the right subclavian artery arising from the aortic arch as the last branch in an 84-year-old Japanese male cadaver. The anomalous artery ran obliquely upward, passed behind the esophagus and trachea, and ultimately ran toward right scalene gap. The area of distribution of the anomalous artery was normal. We report a case of retroesophageal right subclavian artery, and discuss its development, or relation with the thoracic duct, and its clinical importance. Despite this type of variation being relatively rare, reports on such a case have been accumulating. Owing to the recent development of CT and MRI, the number of clinical reports on this anomaly has been increasing.

We investigate the impact of strain on photovoltaic current (Jz) characteristics for iron-doped LiNbO3 (Fe-LN) under visible light illumination by thin-film experiments. The Jz values are demonstrated to be dramatically enhanced for the film with a tensile strain along the Ps direction, which is over 500 times as large as that of the bulk (strain-free) Fe-LN crystals. Density functional theory (DFT) calculations show that the tensile strain increases an off-center displacement of Fe2+ that is opposite to the Ps direction. Our experimental and DFT study demonstrates that the control of the lattice strain is effective in enhancing the photovoltaic effect in the Fe-LN system.

Objective To determine the effects of concomitant methotrexate (MTX) on the incidence of large joint replacement resulting from the progression of large joint destruction in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) inhibitors. Methods A retrospective cohort study was performed using a multicenter registry. In total, 803 patients with RA who received etanercept or adalimumab were included. The first large joint replacement during treatment with etanercept or adalimumab was used as the outcome variable in predictive analyses. The cumulative incidence of large joint replacement was estimated using Kaplan-Meier curves, and the impact of concomitant MTX on the incidence of large joint replacement was assessed with Cox proportional hazards models. Propensity score matching was used to reduce selection bias. Results Of all patients, 601 (75%) received concomitant MTX at a median dosage of 8 mg/week (interquartile range 6–8). A total of 49 patients (62 joints) underwent large joint replacement during treatment with etanercept or adalimumab. The incidence of large joint replacement for patients with concomitant MTX was significantly lower than that for patients without MTX (P < 0.001). Multivariate analysis revealed that concomitant MTX independently predicted large joint replacement (hazard ratio 0.36, 95% confidence interval 0.20–0.65). Additionally, propensity score–matched analysis demonstrated that patients with concomitant MTX had a significantly lower incidence of large joint replacement than those without concomitant MTX (P = 0.032). Conclusion Concomitant MTX reduces the incidence of large joint replacement in patients with RA treated with TNF inhibitors.

This observational retrospective study examined whether abatacept efficacy could be augmented with concomitant methotrexate (MTX) or tacrolimus (TAC) in patients with rheumatoid arthritis (RA) who experienced failure with prior biological disease-modifying antirheumatic drugs (DMARDs) and in whom favorable therapeutic efficacy is difficult to achieve. All patients with a prior biological DMARD history who were treated with abatacept for 52 weeks and registered in a Japanese multicentre registry were included. Clinical efficacy and safety of abatacept according to the concomitant drug used, i.e., none (ABT-mono), MTX (ABT-MTX), and TAC (ABT-TAC), were compared. A greater mean percent change of DAS28-ESR was observed in the ABT-TAC group compared with the ABT-mono group at weeks 12 (-20.5 vs. -5.4 %, p = 0.035) and 24 (-25.0 vs. -11.0 %, p = 0.036). ABT-MTX and ABT-TAC groups had a significantly higher proportion of patients who achieved low disease activity (LDA) within 52 weeks compared with the respective baselines, while no significant change was observed in the ABT-mono group. A higher proportion of patients in the ABT-TAC group achieved EULAR moderate response compared with the ABT-mono group at week 52 (66.7 vs. 35.0 %, p = 0.025). Multivariate logistic regression analysis revealed that concomitant TAC use was independently associated with the achievement of LDA and EULAR response at 52 weeks, while concomitant MTX use was not. Concomitant TAC use may offer a suitable option for RA patients treated with abatacept after prior biological DMARD failure, likely because both abatacept and TAC affect T cell activation.

Tacrolimus (TAC) and abatacept (ABT) inhibit T-cells via different mechanisms and, in combination, may be effective against rheumatoid arthritis. However, they may also disrupt normal immune functions. We compared the efficacy and safety of ABT administered to patients in combination with TAC, methotrexate (MTX), or other drugs.This was a retrospective multicenter study conducted to compare the efficacy and safety of ABT in 211 patients: the drug was administered together with TAC (ABT+ TAC group; 22 patients), MTX (ABT+ MTX group; 102 patients), or patients treated without concomitant MTX or TAC (ABT mono group; 87 patients). The disease activity, treatment continuation rate, and reason for discontinuation of treatment were investigated.The retention rate at Week 24 was similar in the three groups. There were no cases of discontinuation related to the appearance of adverse events in the ABT+ TAC group. At Week 24, according to the European League Against Rheumatism response criteria, the "good" response rates were 33.3%, 13.4%, and 13.4% in the ABT+ TAC, ABT+ MTX, and ABT mono groups, respectively. Statistically significant decreases in various disease activity scores/indices were observed in all the groups as early as Week 4.Although the sample size was small, the results of this retrospective study suggest that the ABT+ TAC combination therapy has at least comparable safety and efficacy to those of the ABT+ MTX combination, and that it can thus be a useful option for patients who cannot take MTX.

Objective.Our study aimed to evaluate the longterm efficacy and safety of abatacept (ABA), and to explore factors that increase its longterm efficacy in patients with rheumatoid arthritis (RA) treated in routine clinical practice.Methods.There were 231 participants with RA treated with ABA who were prospectively registered in a Japanese multicenter registry. They were followed up for at least 52 weeks.Results.Mean age of the patients was 64.3 years, mean disease duration was 12.1 years, mean 28-joint Disease Activity Score (DAS28)-C-reactive protein was 4.49, and 48.5% of patients were concomitantly treated with methotrexate (MTX). Overall retention rate of ABA was 77.1% at 52 weeks; 14.8% of patients discontinued because of inadequate response and 3.5% because of adverse events. The proportion of patients achieving DAS28-defined low disease activity (LDA) significantly increased from baseline to 52 weeks (7.3% to 43.8%, p < 0.01); 40.9% of patients who did not achieve LDA at 24 weeks had more than 1 categorical improvement in DAS28-defined disease activity at 52 weeks. Multivariate logistic regression revealed concomitant MTX use to be an independent predictor of the categorical improvement in DAS28-defined disease activity from 24 to 52 weeks (adjusted OR 3.124, p = 0.010).Conclusion.In routine clinical practice, ABA demonstrated satisfactory clinical efficacy and safety in patients with established RA for 52 weeks. The clinical efficacy of ABA increased with time even after 24 weeks, and this was strongly influenced by concomitant MTX use. Our study provides valuable real-world findings on the longterm management of RA with ABA.

Objective: This study aimed to investigate predictors of biologic discontinuation due to insufficient response as a surrogate for relapse in patients with rheumatoid arthritis (RA) who achieved clinical remission with biologic treatment. Methods: This study was performed based on data from a multicenter registry, and included 404 patients who achieved clinical remission within the first year of treatment with their first biologic. Cumulative retention rate of the first biologic was estimated using Kaplan–Meier curves, and the impact of patient characteristics on biologic discontinuation was assessed with Cox proportional hazards models. Results: During follow-up, 50 patients discontinued their first biologic due to insufficient response. Overall discontinuation rates due to insufficient response after achieving remission were 6%, 11%, and 19% at 1, 2, and 5 years, respectively. Multivariate analysis revealed that concomitant glucocorticoids at achieving remission [hazard ratio (HR): 3.80, 95% confidence interval (CI): 1.89–7.64)] and a higher level of C-reactive protein (CRP) at achieving remission (HR: 1.47 per 1 mg/dL, 95% CI: 1.09–1.99) independently predict discontinuation due to insufficient response after achieving remission. Conclusion: Patients with RA who achieved remission with concomitant glucocorticoid treatment and a higher level of CRP are at high risk of subsequent biologic discontinuation due to insufficient response., Published online: 13 Jul 2017

OBJECTIVE Only a few studies have assessed predictive factors for the long-term efficacy of abatacept. This study aimed to provide clinical evidence of an adequate observational period for predicting low disease activity (LDA) achievement at 52 weeks in RA patients treated with abatacept. METHODS Participants were all patients registered in a Japanese multicentre registry who were treated with abatacept and had at least 52 weeks of follow-up (n = 254). RESULTS Areas under the receiver operating characteristic curves for the 28-joint count with CRP (DAS28-CRP) at each time point for LDA achievement at 52 weeks were: 0.686 (cut-off score: 4.6) at baseline, 0.780 (3.8) at 4 weeks, 0.875 (3.3) at 12 weeks, and 0.900 (3.0) at 24 weeks. Although patients with a DAS28-CRP score < 3.0 at 24 weeks had the highest proportion of LDA achievement at 52 weeks (79.3%), the proportion for those with a score < 3.3 at 12 weeks was comparable (77.2%, P = 0.697). Proportions were significantly lower in patients with a score < 3.8 at 4 weeks or < 4.6 at baseline. Multivariate logistic regression demonstrated that a DAS28 score of < 3.3 at 12 weeks was an independent strong predictor for LDA at 52 weeks (adjusted odds ratio: 15.2, P < 0.001). CONCLUSION Twelve weeks is an adequate observational period to judge the long-term clinical efficacy of abatacept, and is about as early as the period for assessing TNF blockade therapy.

The aim of this study was to compare the efficacy and retention rates of three biologics (abatacept, tocilizumab, and etanercept) after switching from first-course anti-TNF monoclonal antibody therapy. We performed a retrospective multicenter study of 89 patients who underwent second-course biologic therapy for 52 weeks after switching from first-course anti-TNF monoclonal antibody therapy. Patients at baseline had a mean age of 58.7 years, mean disease duration of 9.8 years, and mean clinical disease activity index (CDAI) of 22.4. There was no significant difference between the three drugs, except in rheumatoid factor positivity. Retention rates for abatacept, tocilizumab, and etanercept treatment at 52 weeks were 72.0, 89.5 and 84.6 %, respectively. The evaluation of CDAI indicated no significant difference at 52 weeks among the three drugs. Discontinuation due to all unfavorable causes did not significantly differ among the three drugs in hazard ratio-based evaluations. Our results show that patients treated with abatacept, tocilizumab, and etanercept achieved a high response rate with no significant differences in drug retention rates and clinical efficacy. These drugs represent good therapeutic options for patients with RA who are refractory to anti-TNF monoclonal antibody therapy.

Insulin induces cardioprotection partly via an antiapoptotic effect. However, the optimal timing of insulin administration for the best quality cardioprotection remains unclear. We tested the hypothesis that insulin administered prior to ischemia provides better cardioprotection than insulin administration after ischemia. Isolated rat hearts were prepared using Langendorff method and divided into three groups. The Pre-Ins group (Pre-Ins) received 0.5 U/L insulin prior to 15 min no-flow ischemia for 20 min followed by 20 min of reperfusion. The Post-Ins group (Post-Ins) received 0.5 U/L insulin during the reperfusion period only. The control group (Control) was perfused with KH buffer throughout. The maximum of left ventricular derivative of pressure development (dP/dt(max)) was recorded continuously. Measurements of TNF-αand p-Akt in each time point were assayed by ELISA. After reperfusion, dP/dt(max) in Pre-Ins was elevated, compared with Post-Ins at 10 minutes after reperfusion and Control at all-time points. TNF-αlevels at 5 minutes after reperfusion in the Pre-Ins were lower than the others. After 5 minutes of reperfusion, p-Akt was elevated in Pre-Ins compared with the other groups. Insulin administration prior to ischemia provides better cardioprotection than insulin administration only at reperfusion. TNF-αsuppression is possibly mediated via p-Akt leading to a reduction in contractile myocardial dysfunction.