Effects of whole-body neuromuscular electrical stimulation device on hemodynamics, arrhythmia, and sublingual microcirculation.

Neuromuscular electrical stimulation has been used to treat cardiovascular diseases and other types of muscular dysfunction. A novel whole-body neuromuscular electrical stimulation (WB-NMES) wearable device may be beneficial when combined with voluntary exercises. This study aimed to investigate the safety and effects of the WB-NMES on hemodynamics, arrhythmia, and sublingual microcirculation. The study included 19 healthy Japanese volunteers, aged 22-33 years, who were not using any medication. Electrocardiogram (ECG), echocardiography, and blood sampling were conducted before a 20-min WB-NMES session and at 0 and 10 min after termination of WB-NMES. Their tolerable maximum intensity was recorded using numeric rating scale. Arrhythmia was not detected during neuromuscular electrical stimulation or during 10 min of recovery. Blood pressure, heart rate, left ventricular ejection fraction, and diastolic function remained unchanged; however, mild mitral regurgitation was transiently observed during WB-NMES in a single male participant. A decrease in blood glucose and an increase in blood lactate levels were observed, but no changes in blood fluidity, sublingual microcirculation, blood levels of noradrenaline, or oxidative stress were shown. WB-NMES is safe and effective for decreasing blood glucose and increasing blood lactate levels without changing the blood fluidity or microcirculation in healthy people.

Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations.

Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS) with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs) showing strong associations (P<1×10(-8)) in GWAS were further genotyped in an independent Japanese samples (818 cases and 1,032 controls) and in Korean samples (835 cases and 421 controls). SNP rs987870, located between HLA-DPA1 and HLA-DPB1, was consistently associated with pediatric asthma in 3 independent populations (P(combined) = 2.3×10(-10), odds ratio [OR] = 1.40). HLA-DP allele analysis showed that DPA1*0201 and DPB1*0901, which were in strong linkage disequilibrium, were strongly associated with pediatric asthma (DPA1*0201: P = 5.5×10(-10), OR = 1.52, and DPB1*0901: P = 2.0×10(-7), OR = 1.49). Our findings show that genetic variants in the HLA-DP locus are associated with the risk of pediatric asthma in Asian populations.

Relationship Between Increased Oxygen Uptake and Lactate Production With Progressive Incremental Electrode Skeletal Muscle Stimulation: A Pilot Study.

Background Belt electrode skeletal muscle stimulation (B-SES) is an alternative exercise therapy for those with difficulty performing voluntary exercise. However, it is unknown whether oxygen uptake (VO2) in B-SES is comparable to cardiopulmonary exercise test (CPX) as assessed by voluntary exercise. This study aimed to evaluate oxygen uptake (VO2) and lactate (LA) production in incremental B-SES compared to ergometer CPX and to determine the relationship with ergometer CPX. Methods This study included 10 healthy young Japanese participants. Using a crossover design, all participants underwent incremental B-SES CPX and ergometer CPX using a 20 W ramp. Serum lactic acid concentration (LA) was measured serially before, during, and after B-SES. The tolerability of B-SES was adjusted with the change in LA level (⊿LA). Results Peak VO2 during B-SES (14.1±3.3 mL/kg/min) was significantly lower than ergometer peak VO2 (30.2±6.2 mL/kg/min, P<0.001). B-SES peak VO2 was similar to the anaerobic threshold (AT) VO2 on ergometer CPX (15.1±2.6 mL/kg/min). LA (Rest: 1.4±0.3, Peak: 2.8±0.8 mmol) and plasma noradrenalin (Rest: 0.2±0.1, Peak: 0.4±0.1 ng/mL) levels increased after B-SES. No significant correlation was observed between B-SES peak VO2 and ergometer CPX. However, after adjusting for B-SES, tolerability, it (peak VO2 of B-SES /⊿LA) correlated with peak VO2 (r=0.688, p=0.028) on the ergometer. Conclusion Peak VO2 of the passively progressive B-SES almost reached the AT value of the ergometer CPX without adverse events. Peak VO2 of B-SES adjusted with ⊿LA may be used to predict peak VO2 in ergometer CPX.

Real-World Safety and Tolerability of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis: Interim Report of a Post-Marketing Surveillance in Japan.

INTRODUCTION: Nintedanib is recommended for the treatment of idiopathic pulmonary fibrosis (IPF); however, treatment discontinuation due to adverse events (AEs) is common. A large-scale post-marketing surveillance study is investigating the real-world tolerability/safety of nintedanib in Japanese patients with IPF in routine clinical practice. Here, we report a 12-month interim analysis of this study. METHODS: The study included Japanese patients with IPF who started nintedanib between 31 August 2015 and 25 December 2018. The primary outcome was the frequency of adverse drug reactions (ADRs), defined as AEs for which a causal relationship with nintedanib could not be excluded. The secondary outcome was change from baseline in forced vital capacity (FVC). Outcomes were analysed in patients who stopped ('discontinued' subgroup) and continued ('continued' subgroup) nintedanib after 12 months. A multivariate analysis was performed to determine potential risk factors for treatment discontinuation. RESULTS: Of 5578 patients in the safety analysis set, 2795 (50.1%) discontinued nintedanib within 12 months of treatment initiation. Overall, 3767 patients (67.5%) had ADRs, with 1356 (24.3%) discontinuing nintedanib because of an ADR. Among patients in the 'discontinued' subgroup (n = 2795), 1442 (51.6%) discontinued because of an ADR. The most common ADRs causing discontinuation within 3 and 12 months were hepatic function abnormal (n = 137/730; 18.8%) and diarrhoea (n = 190/1442; 13.2%), respectively. At 12 months, the decrease in FVC from baseline was smaller in the 'continued' versus the 'discontinued' subgroup (adjusted mean ± standard error change - 104.4 ± 10.9 ml vs. - 311.2 ± 29.2 ml). Stage III/IV IPF and FVC < 70% predicted at baseline were risk factors for early treatment discontinuation. CONCLUSION: About 50% of Japanese patients with IPF discontinued nintedanib within the first year of treatment, with worse lung function being associated with an increased risk of early treatment discontinuation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02607722; European Union electronic register of Post-Authorisation Studies: EUPAS10891.

Long-Term Tailor-Made Exercise Intervention Reduces the Risk of Developing Cardiovascular Diseases and All-Cause Mortality in Patients with Diabetic Kidney Disease.

This study aimed to determine the effect of long-term exercise on the risk of developing cardiovascular diseases (CVD) and all-cause mortality in patients with diabetic kidney disease (DKD). A single-center, prospective intervention study using propensity score matching was performed over 24 months. The intervention group (n = 67) received six months of individual exercise instruction from a physical therapist, who performed aerobic and muscle-strengthening exercises under unsupervised conditions. New events were defined as the composite endpoint of stroke or CVD requiring hospitalization, initiation of hemodialysis or peritoneal dialysis, or all-cause mortality. The cumulative survival rate without new events at 24 months was significantly higher in the intervention group (0.881, p = 0.016) than in the control group (n = 67, 0.715). Two-way analysis of variance revealed a significant effect of the group factor on high density lipoprotein-cholesterol (HDL-C) which was higher in the intervention group than in the control group (p = 0.004); eGFRcr showed a significant effect of the time factor, which was lower at 24 months than before intervention (p = 0.043). No interactions were observed for all items. In conclusion, aerobic exercises combined with upper and lower limb muscle strengthening for six months reduce the risk of developing CVD and all-cause mortality in patients with DKD.

Long-term safety and effectiveness of linagliptin as add-on therapy in Japanese patients with type 2 diabetes: final results of a 3-year post-marketing surveillance.

BACKGROUND: We investigated the long-term safety and effectiveness of linagliptin in Japanese type 2 diabetes (T2D) patients starting linagliptin add-on therapy in routine clinical practice. RESEARCH DESIGN AND METHODS: This 3-year prospective, observational, post-marketing surveillance (PMS) was conducted in Japanese patients starting linagliptin add-on therapy. The primary outcome was the incidence of adverse drug reactions (ADRs). The secondary outcome was the change from baseline in HbA1c. RESULTS: The safety analysis set comprised of 3,372 patients. Mean ± standard deviation (SD) age was 66.5 ± 12.4 years. Most patients (63.2%) received linagliptin in combination with another antidiabetic drug, most commonly a sulfonylurea (38.6%). The incidence of ADRs was 11.39%; the most common ADRs according to MedDRA preferred terms were diabetes mellitus (1.25%), hypertension (0.83%), and hypoglycemia (0.80%). In the effectiveness analysis set (n = 3,029), mean ± SD HbA1c was 7.76 ± 1.37% at baseline and 7.26 ± 1.19% at last observation; mean change from baseline to last observation was - 0.49 ± 1.33%; sustained reductions in HbA1c were observed. These results were consistent across patient subgroups. CONCLUSIONS: In this PMS, linagliptin add-on therapy for Japanese T2D patients had a safety profile consistent with its known profile and HbA1c reductions over 3 years were observed. CLINICALTRIALS.GOV: NCT01904383.

Long-Term Safety and Effectiveness of Linagliptin in Japanese Patients with Type 2 Diabetes and Renal Dysfunction: a Post-Marketing Surveillance Study.

INTRODUCTION: International clinical trials have shown that linagliptin significantly improves glycemic control and can be used at a single dose regardless of renal function in patients with type 2 diabetes (T2D). However, to date, no studies have evaluated the use of linagliptin in Japanese patients with T2D by renal function in routine clinical care. METHODS: This was a subgroup analysis of data from a prospective observational post-marketing surveillance (PMS) study of linagliptin conducted in Japan that evaluated the safety and effectiveness of linagliptin in routine clinical care for 3 years in Japanese patients with T2D. The subgroup analysis examined the patient population of this PMS study according to renal function using estimated glomerular filtration rate (eGFR) data. The incidence of linagliptin-related adverse events (adverse drug reactions [ADRs]) was the primary endpoint, and the change in glycated hemoglobin (HbA1c) from baseline to last observation was the secondary endpoint. RESULTS: Of the 2235 patients included in the safety analysis, eGFR was ≥ 90 mL/min/1.73 m2 (defined as group G1) in 16.9% (n = 377), ≥ 60 to < 90 mL/min/1.73 m2 (group G2) in 44.5% (n = 995), ≥ 30 to < 60 mL/min/1.73 m2 (group G3) in 21.7% (n = 486), ≥ 15 to < 30 mL/min/1.73 m2 (group G4) in 2.6% (n = 58) and < 15 mL/min/1.73 m2 (group G5) in 1.7% (n = 37). No eGFR data were available for 12.6% (n = 282) of patients. In these GFR groups, the incidence of ADRs with linagliptin was 6.9% in group G1, 11.1% in group G2, 13.8% in group G3, 15.5% in group G4 and 16.2% in group G5; the change in HbA1c from baseline to the last observation was - 1.11, - 0.64, - 0.35, - 0.46 and - 0.54% in the respective subgroups. CONCLUSIONS: Long-term linagliptin use showed sustained improvements in glycemic control with no new safety concerns regardless of renal function. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01650259). FUNDING: This study was funded by Nippon Boehringer Ingelheim Co., Ltd. and Eli Lilly Japan K.K.

Safety and effectiveness of empagliflozin in Japanese patients with type 2 diabetes: interim analysis from a post-marketing surveillance study.

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective treatments for type 2 diabetes mellitus (T2DM). We present the interim findings of an ongoing post-marketing surveillance (PMS) study in Japanese patients with T2DM receiving empagliflozin.Research design and methods: This 3-year, prospective, observational, multicenter PMS evaluated the safety and effectiveness of empagliflozin in Japanese clinical practice. Patients with T2DM who had not been treated with empagliflozin before enrollment were eligible. Assessments, including the primary endpoint of incidence of adverse drug reactions (ADRs), were based on electronic case report forms (eCRF).Results: Of 8,180 registered patients from 1,103 sites, 7,618 patients had an eCRF including a follow-up visit and were treated (mean age, 58.8 years; 10.5% aged ≥75 years; 63.2% male; mean HbA1c, 8.01%; 41.8% with HbA1c ≥8.0%; 24.8% and 61.8% with at least mild hepatic and renal impairment, respectively). Mean treatment duration was 98.4 weeks; 644 (8.5%) patients had ≥1 ADR, including 8.5% of patients aged ≥75 years. Hypoglycemia, urinary tract infection, genital infections, volume depletion, diabetic ketoacidosis, and lower limb amputation occurred in 0.28%, 0.62%, 0.53%, 0.33%, 0%, and 0.03% of patients, respectively.Conclusions: The reported ADRs were consistent with the known safety profile of empagliflozin.Trial registration: ClinicalTrials.gov identifier: NCT02489942.

Long-Term Safety and Effectiveness of Linagliptin in Japanese Patients with Type 2 Diabetes Mellitus: A 3-Year Post-Marketing Surveillance Study.

INTRODUCTION: Clinical trials of linagliptin in Japanese patients conducted to date have had limited observational periods; therefore, there is a need for additional longer-term real-world data. The aim of this study was to investigate the long-term safety and effectiveness of linagliptin in routine clinical practice. METHODS: This was a prospective, observational, post-marketing surveillance study conducted over 156 weeks in patients with type 2 diabetes mellitus who started linagliptin monotherapy. The primary endpoint was the incidence of adverse drug reactions (ADRs). The secondary endpoint was the change in glycated hemoglobin (HbA1c) from baseline to last available observation. Other effectiveness endpoints included the change in HbA1c and change in fasting plasma glucose (FPG) from baseline to week 26 and over the course of the treatment period. RESULTS: Overall, 2235 and 2054 patients were included in the safety and effectiveness analysis sets, respectively. Patients were mostly male (58.4%), and the mean age was 66.7 years. The incidence of ADRs was 10.7% (n = 240). The most frequent ADRs according to MedDRA preferred terms were diabetes mellitus (n = 35 patients, 1.6%), constipation (n = 21, 0.9%), diabetes mellitus inadequate control (n = 13, 0.6%) and hypertension (n = 13, 0.6%). The mean change in HbA1c from baseline to last observation was - 0.67% [standard deviation (SD) 1.27%, 95% confidence interval - 0.72, - 0.61]. At week 26, HbA1c and FPG showed mean ± SD changes from baseline of - 0.73 ± 1.20% and - 21.02 ± 44.33 mg/dL, respectively, that were sustained until week 156. CONCLUSIONS: In Japanese patients with type 2 diabetes mellitus, linagliptin produced sustained reductions in HbA1c and had a safety profile consistent with the established safety profile of linagliptin. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01650259).

Idarucizumab for Emergency Reversal of Anticoagulant Effects of Dabigatran: Interim Results of a Japanese Post-Marketing Surveillance Study.

INTRODUCTION: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran, and it was approved in Japan in September 2016. An all-case post-marketing surveillance is ongoing to collect data in Japanese patients treated with idarucizumab who had serious bleeding (Group A) or required an urgent procedure (Group B). METHODS: The primary endpoint was the incidence of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effect of dabigatran based on activated partial thromboplastin time (aPTT) within 4 h after idarucizumab administration. RESULTS: This interim analysis included 262 patients who received idarucizumab. Eighteen patients (6.9%) experienced ADRs within 4 weeks. The reversal effect of idarucizumab based on aPTT within 4 h after idarucizumab administration was assessed in 30 patients and the median maximum percentage reversal was 100%. In Group A, the median time to bleeding cessation in patients without intracranial bleeding was 3.3 h. In Group B, normal intraoperative hemostasis was reported in 63 patients (72.4%). CONCLUSIONS: The results of this interim analysis suggest that idarucizumab is safe and effective for the reversal of dabigatran in Japanese patients in a real-world setting, and support the continued use of idarucizumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02946931.

Restoration of innate host defense responses by oral supplementation of branched-chain amino acids in decompensated cirrhotic patients.

AIM: It has been reported that host defense responses, such as phagocytic function of neutrophils and natural killer (NK) cell activity of lymphocytes, are impaired in cirrhotic patients. The aim of the present study was to examine the effects of oral supplementation of branched-chain amino acids (BCAA) on host defense mechanisms in peripheral blood of patients with decompensated cirrhosis. METHODS: Ten patients with decompensated cirrhosis received 12 g BCAA daily for 3 months. Phagocytic function of neutrophils and NK activity of lymphocytes as well as serum albumin levels and Fisher's ratios were determined before and at 1 and 3 months of BCAA supplementation. For quantification of phagocytic function, fluorescent intensities of cells in the neutrophil region in the cytogram were determined by flow cytometry after incubation of whole blood with fluorescent microspheres. NK activity was estimated by (51)Cr release assay using K-562 cell line as target cells. RESULTS: Phagocytic function of neutrophils was significantly improved by 3-month BCAA supplementation (P < 0.01). Thechanges of NK activity were also significant at 3 months of supplementation compared with before supplementation (P < 0.01). Fisher's ratios were significantly increased at 3 months of BCAA supplementation compared with those before oral supplementation (P < 0.05), although the changes of serum albumin level were not statistically significant. CONCLUSIONS: BCAA oral supplementation improved phagocytic function of neutrophils and NK activity of lymphocytes in cirrhotic patients. BCAA supplementation may reduce the risk of bacterial and viral infection in patients with decompensated cirrhosis.

Phagocytic function of neutrophils of patients with decompensated liver cirrhosis is restored by oral supplementation of branched-chain amino acids.

It has been reported that phagocytic function of neutrophils is impaired in cirrhotic patients. We examined the effects of oral supplementation of branched-chain amino acids (BCAA) on phagocytic function of neutrophils in peripheral blood of patients with decompensated cirrhosis. Five patients with decompensated cirrhosis received 12g of BCAA daily for 3 months. Phagocytic function of neutrophils and NK activities of lymphocytes in peripheral blood as well as serum albumin levels and Fisher's ratios were determined before and at 1 and 3 months of BCAA supplementation. Phagocytic function of neutrophils was significantly improved by 3-month BCAA oral supplementation. NK activity of lymphocytes was improved in four of five patients at 3 months of BCAA supplementation, although the changes were not statistically different. In conclusion, BCAA supplementation improved phagocytic function of neutrophils in cirrhotic patients. BCAA supplementation may reduce the risk of bacterial infection in patients with decompensated liver cirrhosis.

Expression of P-glycoprotein in rat hepatocarcinogenesis by diethylnitrosamine and the modulation by anticancer drugs.

P-glycoprotein (P-GP) is known to be a multidrug resistant 1 gene product and to exhibit resistance to a broad range of drugs including anticancer drugs such as epirubicin. Its overexpression is reported in human hepatocellular carcinoma and in adenomatous hyperplasia of the liver as well. In order to clarify the evolution of P-GP expression during hepatocarcinogenesis and its modulation by anticancer drugs, we performed an immunohistochemical study in male Wistar rat livers exposed to diethylnitrosamine (DEN) for 12 weeks. Some rats were pretreated with cisplatin or epirubicin 1 week prior to the exposure, and some rats were treated with them at the 10th week after the exposure. While there was no P-GP expression in the liver of the control, cisplatin, and epirubicin (DEN-free) rats, expression was confirmed in the hepatocytes of DEN-treated rats. The immunostaining of hyperplastic nodules was significantly more intense than in well-differentiated hepatocellular carcinomas, and no staining was observed in poorly-differentiated carcinomas. Markedly intense staining was observed in the early hyperplastic nodules of cisplatin-pretreated rats, as well as in epirubicin-pretreated rats. Plasma alpha-fetoprotein levels were markedly elevated in DEN-treated rats, while tumor necrosis factor-alpha levels were not. In conclusion, the results suggest that P-GP confers a protective effect against anticancer drugs and provides a great advantage to the initiated cells. Furthermore, in addition to epirubicin, cisplatin also promotes the induction of P-GP in the initiated cell.

Clarification of interspousal hepatitis C virus infection in acute hepatitis C patients by molecular evolutionary analyses: Consideration on sexual and non-sexual transmission between spouses.

AIM: Previous studies evaluating the possibilities of interspousal sexual transmission of hepatitis C virus (HCV) have yielded many conflicting results. The aim of this study was to clarify the source of HCV infection in acute hepatitis C patients using phylogenetic analyses of nucleotide sequences of HCV E1 region. METHODS: Four acute hepatitis C patients were hospitalized in 2002-2007. The diagnosis was based on medical records, laboratory tests including HCV markers, and ultrasonographic examination of the liver. In each spouse of four patients, serum HCV antibody was assayed. In the subjects whose serum HCV antibody was positive, additional tests on HCV viral load and genotype were carried out. Then phylogenetic analyses of nucleotide sequences of partial HCV E1 region (440 nucleotides) of the patients and their spouses were performed. RESULTS: Hepatitis C virus antibody changed from negative to positive in the course of hospitalization and HCV RNA could be detected in every patient. Therefore they were diagnosed as acute hepatitis caused by HCV infection. In every spouse of four patients, HCV antibody and HCV RNA were positive. Three of four couples had the identical genotype and homogeneity of nucleotide sequences of HCV E1 region in three couples ranged from 97.9% to 100%. The results of phylogenic analyses suggested that interspousal HCV infection occurred in the three couples. CONCLUSION: In conclusion, interspousal infection might be one of the important sources of acute HCV infection in Japan. The usefulness of phylogenetic analysis of nucleotide sequences of HCV E1 region for clarifying interspousal HCV infection was validated.

Hepatocellular carcinoma with direct invasion to the stomach.

A 71-year-old man was admitted to our hospital with abdominal pain. Hepatocellular carcinoma (HCC) had been diagnosed 2 years earlier and he had undergone 7 courses of intra-hepato-arterial chemotherapy (IHAC). We performed gastrointestinal fiberscopy and identified a massive protrusion on the lesser curvature. Abdominal contrast-enhanced computed tomography revealed multiple hepatic masses and an extrahepatic enlarged mass with invasion to the pancreas and stomach. A specimen for endoscopic biopsy revealed adenocarcinoma that stained positive for alpha-fetoprotein. Gastrointestinal bleeding resulting from direct invasion of HCC is unusual.