Bortezomib-cyclophosphamide-dexamethasone induction/consolidation and bortezomib maintenance for transplant-eligible newly diagnosed multiple myeloma: phase 2 multicenter trial.

OBJECTIVES: We conducted a phase II trial to prospectively evaluate the efficacy and safety of bortezomib-cyclophosphamide-dexamethasone (VCD) induction, autologous stem cell transplantation (ASCT), VCD consolidation, and bortezomib maintenance in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients in Japan (UMIN000010542). METHODS: From 2013 to 2016, 42 patients with a median age of 58 (range 42-65) years with NDMM were enrolled in 15 centers. The primary endpoint was the complete response (CR) /stringent CR (sCR) rate after transplantation, and overall/progression-free survival rates were also evaluated. RESULTS: Following induction therapy, the overall response rate was obtained in 71% of patients, including a CR/sCR of 10% and a very good partial response (VGPR) of 26%. Twenty-six of the 42 patients completed ASCT following the protocol and CR/sCR and VGPR rate 100 days after ASCT was 26% and 17%, respectively. During consolidation therapy, 3 of the 24 patients achieved deeper responses. Eight of the 18 patients completed 2-year bortezomib maintenance without disease progression and grade 3/4 toxicities. Five patients were VGPR or partial response after ASCT but maintained response with 2-year bortezomib maintenance. Two-year overall and progression-free survival rates were 92.5% (95% confidence interval [CI]: 78.5%-97.5%) and 62.6% (95% CI: 45.8%-75.5%), respectively. Grade 3/4 toxicities (≥ 10%) included neutropenia (19%) and anemia (17%) in induction, and thrombocytopenia (29%) in consolidation. CONCLUSION: VCD induction/consolidation and bortezomib maintenance with ASCT for NDMM resulted in a high CR/sCR rate and provided good overall/progression-free survival in Japan.

The effect of the Original MethOd at pharmacy To ENhAnce Support for Health Improvement in the limited Japanese proficiency patients visiting local community pharmacy: A randomized controlled trial.

OBJECTIVES: With an increase in globalization, the number of non-native-speaking citizens and tourists visiting local pharmacies is rapidly growing worldwide, creating linguistic and sociological problems. The aim of this study is to compare the effect of adding our original method, Original MethOd at pharmacy To ENhAnce Support for Health Improvement (OMOTENASHI), to the conventional medication counselling method (CMC) when counselling non-Japanese patients at the pharmacy. METHODS: The OMOTENASHI consists of tools written in multiple languages and illustrations to clarify the effects and side effects, and to confirm patients' understanding. 71 non-Japanese patients were recruited and randomly assigned to the OMOTENASHI or to the CMC in a 1:1 ratio. Comprehension and satisfaction level were evaluated. RESULTS: The overall comprehension level was significantly higher in the OMOTENASHI than in the CMC (75% vs 38%, p = 0.002), with a prominent difference in the recognition of the name, effects, side effects, precautions, and how to deal with side effects of the prescribed medication. CONCLUSION: The OMOTENASHI to be a helpful tool in providing essential information to non-native-speaking patients. PRACTICE IMPLICATION: The study highlighted the need to ensure every patient's safety and interests, and to avoid disadvantages caused by limited language proficiency in the globalization era.

Performance Index for Types of Clinical Research Support Service Providers for Academic Research Organizations in Japan: A Cross-Sectional Survey.

The purpose of this study was to conduct a factual survey to evaluate the type of clinical research support offered by service providers (supporters) in Japanese academic research organizations (AROs). From September to October 2018, we conducted an online questionnaire targeting researchers and supporters of AROs, including individuals supporting research and development (R&D) planning, as well as those involved in study management, biostatistics, coordination, data management, monitoring, and auditing. The number of responses was tabulated for each survey item. For items with written descriptions, we compiled summaries using the inductive regression method of qualitative research. Responses were obtained from 124 researchers, 258 supporters, and 40 AROs. None of the institutions responded that they had a performance index for all types of service providers, whereas 47% of institutions had an index for 1-3 types of service providers, and 40% of institutions had no index. Many institutions responded that they had a performance index for coordinators and data management, but few responded that there was a performance index for individuals engaged in R&D and study management. Furthermore, for all evaluations of AROs and researchers, the level of supporter satisfaction was low at only 20%. There was a discrepancy between the levels of researcher expectations and the actual contribution of R&D in the process of research planning. Our survey revealed that there is currently no performance index for services supporting clinical research. In future studies, we need to examine a performance index that accurately reflects the researcher attitudes revealed in this study.

Associations between visceral obesity and renal impairment in health checkup participants: a retrospective cohort study.

BACKGROUND: Obesity is a risk factor for chronic kidney disease. Although body mass index (BMI) or waist circumference is indicators of obesity, actual measurements of visceral fat area (VFA) more accurately reflect the amount of visceral fat. We aimed to determine the most sensitive obesity indicator for predicting renal impairment among VFA, BMI, waist circumference, waist-to-height ratio, and visceral-to-subcutaneous fat ratio (VSR). METHODS: Subjects who underwent VFA measurements during health checkups in 2012 were included. Obesity was defined using a separate baseline value for each indicator [VFA (100 cm2), BMI (25 kg/m2), waist circumference (85 cm for men and 90 cm for women), waist-to-height ratio (0.5), VSR (0.4)]. Changes in estimated glomerular filtration rate (eGFRcr) and time to new-onset proteinuria were measured. The relationships between obesity indicators and eGFRcr were evaluated using a linear mixed-effects model. The relationships between obesity indicators and new-onset proteinuria were evaluated using Poisson regression analysis. RESULTS: Analysis was performed on 2753 subjects (mean age 50.3 years). The VFA ≥ 100 cm2 group exhibited a larger annual difference in eGFRcr compared to the < 100 cm2 group (- 0.24 mL/min/1.73 m2, P = 0.03). There was a statistically significant difference in the proteinuria incidence rate ratio, which was 1.54 times (95% confidence interval 1.01-2.35) in the VFA ≥ 100 cm2 group. Statistically significant correlations were not observed with any of the other obesity indicators. CONCLUSION: VFA is suggested to be the most sensitive obesity indicator for decline in kidney function and new-onset proteinuria.

Rationale and design of the EMPYREAN study.

AIMS: A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA-REG OUTCOME trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus. METHODS AND RESULTS: This ongoing study is a prospective, randomized, open-label, multicentre investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are conducted using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non-linear least squares method for square analysis. The primary endpoint is the change in the low-frequency (0.04-0.15 Hz)/high-frequency (0.15-0.4 Hz) ratio from baseline to 24 weeks. CONCLUSIONS: This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes.

Dose-response of rPMS for upper Limb hemiparesis after stroke.

INTRODUCTION: Repetitive peripheral magnetic stimulation (rPMS) therapy is an innovative and minimally invasive neurorehabilitative technique and has been shown to facilitate neural plasticity. However, there is at present no research that clarifies the dose-response of rPMS therapy on the recovery of upper limb hemiparesis after stroke. This trial aims to clarify the dose-response of rPMS therapy combined with intensive occupational therapy (OT) for chronic stroke patients with moderate to severe upper limb hemiparesis. METHODS AND ANALYSIS: This multicenter, prospective, assessor-blinded, randomized controlled study with 3 parallel groups will be conducted from January 20, 2020 to September 30, 2022. Fifty patients will be randomly assigned in a ratio of 1:2:2 to the control group, the group receiving daily 2400 pulses of rPMS, or the group receiving daily 4800 pulses of rPMS, respectively. From the day after admission (Day 1), rPMS therapy and intensive OT will be initiated. The primary outcome is the change in the motor function of the affected upper extremity (Fugl-Meyer Assessment) between the time of admission (Day 0) and the day after 2 weeks of treatment (Day 14). Secondary outcomes will include the changes in spasticity, active range of motion, motor evoked potential, and activity of daily living. ETHICS AND DISSEMINATION: The study was approved by the Jikei University Certified Review Board for all institutions (reference number: JKI19-020). Results of the primary and secondary outcomes will be published in a peer-reviewed journal and presented at international congresses. The results will also be disseminated to patients. TRIAL REGISTRATION NUMBER: jRCTs032190191.

Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients: extended follow-up of JBCRG-cohort study 01.

BACKGROUND: Previous large trials of trastuzumab (TZM) demonstrated improved outcomes in patients with HER2-positive early breast cancer. However, its effectiveness and safety in Japanese patients is not yet clear. Recently, new anti-HER2 agents were developed to improve treatment outcomes, but the patient selection criteria remain controversial. PURPOSE: The aim of this study was to evaluate the long-term effectiveness of TZM therapy as perioperative therapy for HER2-positive operable breast cancer in daily clinical practice and to create a recurrence prediction model for therapeutic selection. METHODS: An observational study was conducted in Japan (UMIN000002737) to observe the prognosis of women (n = 2024) with HER2-positive invasive breast cancer who received TZM for stage I-III C disease between July 2009 and June 2011. Moreover, a recurrence-predicting model was designed to evaluate the risk factors for recurrence. RESULTS: The 5- and 10-year disease-free survival (DFS) rates were 88.9 (95% CI 87.5-90.3%) and 82.4% (95% CI 79.2-85.6%), respectively. The 5- and 10-year overall survival (OS) rates were 96% (95% CI 95.1-96.9%) and 92.7% (95% CI 91.1-94.3%), respectively. Multivariate analysis revealed that the risk factors for recurrence were an age of ≥ 70 years, T2 or larger tumors, clinically detected lymph node metastasis, histological tumor diameter of > 1 cm, histologically detected lymph node metastasis (≥ n2), and the implementation of preoperative treatment. The 5-year recurrence rate under the standard treatment was estimated to be > 10% in patients with a score of 3 or greater on the recurrence-predicting model. CONCLUSION: The recurrence-predicting model designed in this study may improve treatment selection of patients with stage I-III C disease. However, further studies are needed to validate the scores generated by this model.

The association between uric acid levels and renal function of CKD patients with hyperlipidemia: a sub-analysis of the ASUCA trial.

BACKGROUND: The influence of uric acid (UA) on renal function and the significance of UA-lowering therapy are unclear. The purpose of the sub-analysis of the Assessment of Clinical Usefulness in chronic kidney disease patients with Atorvastatin (ASUCA) trial was to evaluate the influence of serum UA levels on renal function in Japanese chronic kidney disease patients with hyperlipidemia. METHODS: Of 344 participants in the ASUCA trial, 279 participants whose UA levels at both baseline and 24 months were available were included. Based on UA level at baseline or mean UA level during the trial period, they were divided into four groups: < 5.0, 5.0-6.0, 6.0-7.0, or ≥ 7.0 mg/dL, irrespective of allocation. Changes in the estimated glomerular filtration rate (eGFR) after 24 months were compared among the groups in relation to baseline or mean UA levels. RESULTS: For baseline UA levels (< 5.0, 5.0-6.0, 6.0-7.0, or ≥ 7.0 mg/dL), the change in eGFR after 24 months was - 1.32 ± 10.3, - 1.74 ± 8.94, - 2.53 ± 7.34, and - 3.51 ± 9.10 mL/min/1.73 m2, respectively. A negative correlation between changes in eGFR after 24 months and baseline UA level was observed with adjustment for confounding factors. The relationship between changes in eGFR and mean UA levels during trial period showed a similar trend. CONCLUSION: In CKD patients with dyslipidemia, hyperuricemia was an independent risk factor for CKD progression. An ongoing clinical trial (TARGET-UA, UMIN-ID 000,026,741) may reveal the significance of strict UA-lowering therapy in CKD patients.

Importance of Quality Assessment in Clinical Research in Japan.

Background: The number of papers published by an institution is acknowledged as an easy-to-understand research outcome. However, the quantity as well as the quality of research papers needs to be assessed. Methods: To determine the relation between the number of published papers and paper quality, a survey was conducted to assess publications focusing on interventional clinical trials reported by 11 core clinical research hospitals. A score was calculated for each paper using Système d'interrogation, de gestionet d'analyse des publications scientifiques scoring system, allowing for a clinical paper quality assessment independent of the field. Paper quality was defined as the relative Journal impact factor (IF) total score/number of papers. Results: We surveyed 580 clinical trial papers. For each of the 11 medical institutions (a-k), respectively, the following was found: number of published papers: a:66, b:64, c:61, d:56, e:54, f:51, g:46, h:46, i:46, j:45, k:45 (median: 51, maximum: 66, minimum: 45); total Journal IF: a:204, b:252, c:207, d:225, e:257, f:164, g:216, h:190, i:156, j:179, k:219 (median: 207, maximum: 257, minimum: 156); relative Journal IF total score: a:244, b:272, c:260, d:299, e:268, f:215, g:225, h:208, i:189, j:223, k:218 (median: 225, maximum: 299, minimum: 189); and paper quality (relative Journal IF total score/number of papers): a:3.70, b:4.25, c:4.26, d:5.34, e:4.96, f:4.22, g:4.89, h:4.52, i:4.11, j:4.96, k:4.84 (median: 4.52, maximum: 5.34, minimum: 3.70). Additionally, no significant relation was found between the number of published papers and paper quality (correlation coefficient, -0.33, P = 0.32). Conclusions: The number of published papers does not correspond to paper quality. When assessing an institution's ability to perform clinical research, an assessment of paper quality should be included along with the number of published papers.

Cross-sectional study of the association between day-to-day home blood pressure variability and visceral fat area measured using the dual impedance method.

BACKGROUND: The blood pressure (BP) variability (BPV) is a predictor of cardiovascular disease, independently of the BP itself. In addition, visceral fat accumulation can trigger atherosclerotic disease through various mechanisms. METHODS AND RESULTS: We examined the association between fat accumulation and day-to-day BPV in 61 adult hypertensive patients. Visceral fat area (VFA) was measured using the dual bioelectrical impedance analysis method. Participants were divided into three groups based on VFA. The standard deviation (SD) in home systolic BP (SBP) for 7 consecutive days was significantly lower in the high VFA tertile (low VFA, 8.40±4.15 mmHg; intermediate VFA, 8.47±2.80 mmHg; and high VFA, 5.84±2.37 mmHg, p of One-way ANOVA = 0.017, p for trend = 0.0126). A similar association was observed between the coefficient of variance (CV) of home SBP and the VFA tertile. Multiple-regression analysis adjusted for age, sex, antihypertensive drug, diabetes, habitual drinking, and SBP level also showed a significant association between the VFA tertile and the SD or CV of home SBP. The adjusted coefficient of regression for the SD of home SBP was -3.28 (95%CI: -5.60 to -0.97, p = 0.008) and the CV of home SBP was -2.51 (95%CI: -4.31 to -0.71, p = 0.008) for the highest VFA tertile as compared to the lowest VFA tertile. CONCLUSIONS: These results show for the first time negative correlation between VFA and day-to-day BPV. The degree of obesity should be taken into account when evaluating the value of BPV.

Survival Outcomes of Retreatment with Trastuzumab and Cytotoxic Chemotherapy for HER2-Positive Recurrent Patients With Breast Cancer Who Had Been Treated with Neo/adjuvant Trastuzumab Plus Multidrug Chemotherapy: A Japanese Multicenter Observational Study.

BACKGROUND: There are little data on the usefulness of trastuzumab (TZM) retreatment as the first-line treatment for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer recurrence after perioperative treatment with TZM. AIM: To clarify the outcome and safety of TZM retreatment in patients with recurrent HER2-positive breast cancer. METHOD: An observational study was conducted on patients who relapsed after primary systemic therapy with TZM using the central registration system. The primary end point was progression-free survival (PFS). Secondary end points consisted of the response rate, overall survival (OS), and safety. RESULT: In total, 34 patients were registered between July 2009 and June 2012. The median follow-up time was 23.7 months (2-24 months). The 1- and 2-year PFS rates were 46.9% (95% confidence interval (95% CI): 29.2%-62.9%) and 29.8% (95% CI: 15.0%-46.3%), respectively (median 10.6 months). The median PFS time for patients receiving TZM combined with CTx was 13.9 months. The 1-and 2-year OR rates were 93.9 (95% CI: 77.9%-98.4%) and 84.8% (95% CI: 67.4%-93.4%). Trastuzumab-induced grade 3/4 adverse events were not observed. CONCLUSIONS: This study suggests that the PFS and OS in Japanese patients who relapsed after perioperative TZM therapy improved or were similar to those in previous reports. Differences in patient backgrounds and treatments must be considered when interpreting the results. Trastuzumab should be used combination with CTx and/or HTx for retreatment. Retreatment with TZM is safe.Trial registration: UMIN000002738.

Long-term effects of antihypertensive therapy on cardiovascular events and new-onset diabetes mellitus in high-risk hypertensive patients in Japan.

OBJECTIVE: During the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, patients with hypertension who received amlodipine had similar cardiovascular risks as those who received candesartan. We conducted a post-trial study, the Candesartan Antihypertensive Survival Evaluation in Japan 10-year follow-up (CASE-J 10). This study aimed to confirm the long-term cardiovascular effects of candesartan and amlodipine. METHODS: Case report forms were sent to CASE-J investigators who agreed to participate in the CASE-J 10. All the available information was retrospectively collected. The primary endpoint was a time-to-first event for a composite of cerebrovascular, cardiac, renal, and vascular events, and sudden death. Secondary endpoints included new-onset diabetes (NOD), cardiovascular mortality, and all-cause mortality. For each endpoint, treatment effect was compared on an intention-to-treat basis, according to previous randomization categories. RESULTS: A total of 1313 patients' data have been updated. The 10-year Kaplan-Meier rates of the primary endpoint were 14.7% for candesartan and 14.8% for amlodipine. After adjusting for baseline characteristics, the rates for the primary endpoint were similar between the two treatments (hazards ratioadj = 0.99, 95% CI 0.82-1.20). Candesartan had a lower Kaplan-Meier rate of NOD than amlodipine (8.3 vs. 11.1%), and when adjusted for clinical factors, candesartan remained an independent predictor for NOD prevention (hazard ratioadj = 0.71, 95% CI 0.52-0.98). CONCLUSION: With more than 28 385 patient-years follow-up, we demonstrated that candesartan and amlodipine were comparable in reducing cardiovascular events in patients with high-risk hypertension. Additionally, our results may support candesartan's superiority in reducing NOD incidence compared with amlodipine even after the long-term follow-up.

Effectiveness of nationwide screening and lifestyle intervention for abdominal obesity and cardiometabolic risks in Japan: The metabolic syndrome and comprehensive lifestyle intervention study on nationwide database in Japan (MetS ACTION-J study).

BACKGROUND: Lifestyle interventions can substantially improve obesity and cardiometabolic risks. However, evidence of long-term benefits of national intervention is sparse. We aimed to evaluate the long-term effectiveness of a nationwide program for abdominal obesity. METHODS: A retrospective cohort study was performed using a longitudinal nationwide individual data in subjects aged 40-74 years who underwent checkups in fiscal year (FY) 2008. Lifestyle interventions were provided via interview in subjects with abdominal obesity and at least one cardiometabolic risk factor. Subjects who attended the lifestyle intervention (participants) were compared to those who did not attend (non-participants). Outcomes were waist circumferences (WC) and body mass index (BMI) reduction, reversal of metabolic syndrome (MetS), and changes in cardiometabolic risks. We used a three-step process with robust analytic approaches to account for selection bias that included traditional multivariate analysis, propensity-score matching and instrumental variable (IV) analyses. RESULTS: Of 19,969,722 subjects, 4,370,042 were eligible for analyses; 111,779 participants and 907,909 non-participants. A higher percentage of participants had ≥5% reductions in obesity profiles at year 3, compared to non-participants (WC, 21.4% vs 16.1%; BMI, 17.6% vs 13.6%; p<0.001 each). Participants also had higher reversal for MetS (adjusted odds ratio 1.31; 95% confidence interval: 1.29-1.33; p<0.001). Greater reductions in cardiometabolic risks were observed in participants. Those results were confirmed in analyses using a propensity score-matched cohort (n = 75,777, each) and IV analyses. Limitations of this work include the use of non-randomized national data in Japan to assess the effectiveness of the nationwide preventive program. CONCLUSIONS: In the nationwide lifestyle intervention for abdominal obesity, the at-risk population achieved significant reductions in WC, BMI, and cardiometabolic risks in 3 years. This study provides evidence that the nationwide program effectively achieved long-term improvement in abdominal obesity and cardiometabolic risks.

Endothelium-Derived C-Type Natriuretic Peptide Contributes to Blood Pressure Regulation by Maintaining Endothelial Integrity.

We previously reported the secretion of C-type natriuretic peptide (CNP) from vascular endothelial cells and proposed the existence of a vascular natriuretic peptide system composed of endothelial CNP and smooth muscle guanylyl cyclase-B (GC-B), the CNP receptor, and involved in the regulation of vascular tone, remodeling, and regeneration. In this study, we assessed the functional significance of this system in the regulation of blood pressure in vivo using vascular endothelial cell-specific CNP knockout and vascular smooth muscle cell-specific GC-B knockout mice. These mice showed neither the skeletal abnormality nor the early mortality observed in systemic CNP or GC-B knockout mice. Endothelial cell-specific CNP knockout mice exhibited significantly increased blood pressures and an enhanced acute hypertensive response to nitric oxide synthetase inhibition. Acetylcholine-induced, endothelium-dependent vasorelaxation was impaired in rings of mesenteric artery isolated from endothelial cell-specific CNP knockout mice. In addition, endothelin-1 gene expression was enhanced in pulmonary vascular endothelial cells from endothelial cell-specific CNP knockout mice, which also showed significantly higher plasma endothelin-1 concentrations and a greater reduction in blood pressure in response to an endothelin receptor antagonist than their control littermates. By contrast, vascular smooth muscle cell-specific GC-B knockout mice exhibited blood pressures similar to control mice, and acetylcholine-induced vasorelaxation was preserved in their isolated mesenteric arteries. Nonetheless, CNP-induced acute vasorelaxation was nearly completely abolished in mesenteric arteries from vascular smooth muscle cell-specific GC-B knockout mice. These results demonstrate that endothelium-derived CNP contributes to the chronic regulation of vascular tone and systemic blood pressure by maintaining endothelial function independently of vascular smooth muscle GC-B.

Effects of atorvastatin on renal function in patients with dyslipidemia and chronic kidney disease: assessment of clinical usefulness in CKD patients with atorvastatin (ASUCA) trial.

BACKGROUND: Dyslipidemia is a risk factor for the progression of chronic kidney disease (CKD). While conventional lipid lowering therapy provides a benefit to CKD management, the effect of statins on eGFR remains unclear. METHODS: A prospective, multi-center, open-labeled, randomized trial. Total of 349 CKD patients with hyperlipidemia were randomized into 2 groups, and followed for 2 years. Group A included patients who were treated with atorvastatin. Group C were treated with conventional lipid lowering drugs other than statin. Primary endpoint was changes in eGFR. Secondary endpoints included changes in urinary albumin excretion, serum LDL-C, serum triglyceride, cardio-vascular events and all-cause mortality. RESULTS: As the primary endpoint, eGFR decreased by 2.3 ml/min/1.73 m2 in Group A and by 2.6 ml/min/1.73 m2 in Group C, indicating that there was no difference in change of eGFR between the two groups. As secondary endpoints, atorvastatin succeeded to reduce serum LDL-C level significantly and rapidly, but conventional therapy did not. In fact, mean LDL-C level did not reach the target level of 100 mg/dl in Group C. Serum triglyceride was lowered only by atorvastatin, but not conventional drugs. The number of cardiovascular events and all-cause mortality did not differ between in two groups. CONCLUSION: The ASUCA (Assessment of Clinical Usefulness in CKD Patients with Atorvastatin) trial demonstrated that atorvastatin failed to exhibit reno-protections compared to conventional therapy in Japanese patients with dyslipidemia and CKD. It would be due in part to the ability of atorvastatin to more potently reduce serum LDL and triglycerides compared to conventional therapy.

Overall safety and efficacy of high-dose and low-dose intravenous glucocorticoid therapy in patients with moderate-to-severe active Graves' ophthalmopathy.

The objective of this study was to compare the safety and efficacy of high-dose and low-dose intravenous (iv) glucocorticoid (GC) therapy in patients with Graves' ophthalmopathy (GO) and to investigate which factors may help determine appropriate iv GC doses. The medical records of 43 patients who received different doses of iv GCs for GO were retrospectively reviewed. Twenty patients received high-dose iv GCs (HD group, cumulative dose 9.0-12.0 g) and 18 received low-dose iv GCs (LD group, cumulative dose 4.5 g). Five patients with previous treatment for GO were excluded. Changes in ophthalmic parameters after treatment and frequencies of adverse effects due to GCs of the 2 groups were compared. We also reviewed the incidence of GO progression and hepatic dysfunction after patients were discharged. We evaluated correlations among pretreatment (before treatment) ophthalmic parameters and investigated useful predictive factors for determining iv GC doses. There were no significant differences in ophthalmic parameters reflecting treatment efficacy or overall safety between the groups. Among baseline ophthalmic parameters, corrected signal intensity ratio (cSIR) correlated well with magnetic resonance imaging findings and were more strongly associated with changes in ophthalmic parameters after treatment in the HD group than in the LD group, indicating that pretreatment cSIR might be useful for determining iv GC doses. In conclusion, there were no significant differences in overall safety and efficacy between high-dose and low-dose iv GC therapy in patients with active GO. Further randomized clinical trials with longer observation periods are required to establish the optimal treatment regimen of GO.

Optimal timing of surgery for active infective endocarditis with cerebral complications: a Japanese multicentre study.

OBJECTIVES: The aim of this study was to investigate the effect of the timing of valve surgery on the clinical outcomes of patients with active infective endocarditis (IE) accompanied by cerebral complications. METHODS: We retrospectively analysed a cohort of 568 patients, comprising 118 with non-haemorrhagic cerebral infarction (CI), 54 with intracranial haemorrhage (ICH) and 396 without cerebral events (C; control), who underwent surgery for left-sided active IE in 15 Japanese institutes from 2000 to 2011. The mean age was 58.4 ± 16.9 years in the CI group; 54.5 ± 17.4 years in the ICH group and 56.9 ± 16.0 years in the C group. Clinical outcomes were analysed according to the timing of surgery after the diagnosis of CI or ICH was made. RESULTS: In the CI group, there were 9 (7.6%) hospital deaths, 13 (11%) new cerebral events and 1 (0.8%) redo valve surgery. In the ICH group, there were 3 (5.6%) hospital deaths, 8 (14.8%) new cerebral events and 2 (3.7%) redo valve surgeries. In the C group, there were 36 (9.1%) hospital deaths, 23 (5.8%) new cerebral events and 9 (2.3%) redo valve surgeries. Risk factors for hospital death were prosthetic valve endocarditis (P = 0.045), high C-reactive protein (CRP; P < 0.001) and the elderly (P < 0.001) in the CI group. Delayed surgery (2 weeks after CI) seemed result in a higher incidence of hospital death in the CI group. Patients who had surgery between 15 and 28 days or after 29 days from the onset of CI had higher incidences of hospital death [odds ratio 5.90 (P = 0.107) and 4.92 (P = 0.137), respectively] compared with those who had surgery within 7 days. In the ICH group, risk factors for hospital death were high CRP (P = 0.002) and elderly (P < 0.001). Contrary to CI patients, patients who had surgery between 8 and 21 days or after 22 days after the onset of ICH had lower incidences of hospital death [odds ratio 0.79 (P = 0.843) and 0.12 (P = 0.200), respectively] compared with those who had surgery within 7 days. CONCLUSIONS: Although statistically insignificant, early surgery in active IE patients with CI is safe, but very early surgery (within 7 days) should be avoided in patients with ICH.

Effects of nocturnal oxygen therapy in patients with chronic heart failure and central sleep apnea: CHF-HOT study.

It was previously reported that nocturnal home oxygen therapy (HOT) significantly improved not only sleep disordered breathing (SDB), but also quality of life (QOL) and left ventricular ejection fraction (LVEF) in two trials. To strengthen the statistical reliability of the above efficacies of HOT and to assess the effects of 12-week nocturnal HOT on suppression of ventricular arrhythmias, we combined the two trials and undertook a post hoc analysis. Ninety-seven patients with chronic heart failure (CHF) and central sleep apnea were assigned to receive HOT (45 patients) or not (52 patients). HOT resulted in greater reduction in the apnea-hypopnea index (AHI) (-11.4 ± 11.0 vs. -0.2 ± 7.6 events/h, p < 0.01), which is associated with greater improvement in the Specific Activity Scale (0.8 ± 1.2 vs. 0.0 ± 0.6, p < 0.01), New York Heart Association (NYHA) functional class (p < 0.01), and LVEF (p = 0.06). Median number of premature ventricular contraction (PVC) at baseline was 17 beats per hour in both the HOT and the control groups. Overall improvements of PVCs were not different either in the HOT group or in the control. However, in 12 patients with NYHA >III and AHI >20 events/h, PVC was significantly improved by HOT with a marked reduction in AHI and a substantial increase in LVEF. In conclusion, among patients with CHF and CSA, HOT improves SDB, QOL, and cardiac function. The effectiveness of HOT for ventricular arrhythmias was not observed in the overall analysis, but only in a limited number of patients with severe CHF and SDB. To clarify the effects of HOT on ventricular arrhythmias in patients with CHF and SDB, a further study is needed.

Holter monitoring for the screening of cardiac disease in diabetes mellitus: The non-invasive Holter monitoring observation of new cardiac events in diabetics study.

We investigated the usefulness of Holter monitoring to detect cardiac disease and predict future cardiovascular risk in asymptomatic diabetic patients. This is a multi-centre, prospective study in 406 asymptomatic diabetic patients. They were categorized into three groups based on findings of Holter monitoring. A total of 377 met inclusion criteria and were classified as low (n = 172), moderate (n = 136) and high risk (n = 69). In total, 86 in moderate and 53 in high risk receive further evaluation. In total, 29 in moderate and 25 in high risk were diagnosed as cardiac disease and 12 required additional treatment, including coronary intervention. Over 1.8 years of mean follow-up, 11 (16.5 per 1000 person-years) experienced cardiovascular events. The cumulative incidence in moderate and high risk was higher than that in low risk (p = 0.029 and p = 0.014, respectively). Our study suggests that Holter monitoring may be a useful screening tool to detect cardiac disease and predict future cardiovascular risk in asymptomatic diabetic patients.