Association of a Transitional Heart Failure Management Program With Readmission and End-of-Life Care in Rural Japan.

Background: Evidence on transitional care for heart failure (HF) in Japan is limited. Methods and Results: We implemented a transitional HF management program in rural Japan in 2019. This involved collaboration with general practitioners or nursing care facilities and included symptom monitoring by medical/nursing staff using a handbook; standardized discharge care planning and information sharing on self-care and advance care planning using a collaborative sheet; and sharing expertise on HF management via manuals. We compared the outcomes within 1 year of discharge among patients hospitalized with HF in the 2 years before program implementation (2017-2018; historical control, n=198), in the first 2 years after program implementation (2019-2020; Intervention Phase 1, n=205), and in the second 2 years, following program revision and regional dissemination (2021-2022; Intervention Phase 2, n=195). HF readmission rates gradually decreased over Phases 1 and 2 (P<0.05). This association was consistent regardless of physician expertise, follow-up institution, or the use of nursing care services (P>0.1 for interaction). Mortality rates remained unchanged, but significantly more patients received end-of-life care at home in Phase 2 than before (P<0.05). Conclusions: The implementation of a transitional care program was associated with decreased HF readmissions and increased end-of-life care at home for HF patients in rural Japan.

Pharmacokinetics of Brexpiprazole, Quetiapine, Risperidone, and Its Active Metabolite Paliperidone in a Postpartum Woman and Her Baby.

BACKGROUND: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine. METHODS: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery. RESULTS: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%. CONCLUSIONS: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%.

Population pharmacokinetics of everolimus in renal transplant recipients receiving long-term multiple immunosuppressive therapy.

Everolimus is used for immunosuppression after renal transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model of everolimus using therapeutic drug monitoring (TDM) data of patients under long-term multiple immunosuppressive therapy, including tacrolimus. To develop the model, 185 renal transplant recipients with 3358 everolimus blood concentrations during a median postoperative period of 35.3 months were included. The PopPK model is described as a one-compartment model with first-order absorption. The population mean of apparent clearance is 8.92 L/h (relative standard error = 3.6%), and this negatively correlated with the dose-normalized concentration (C/D) of tacrolimus and hematocrit value, and positively correlated with a daily dose of everolimus (i.e. TDM effect). The usefulness of dose adjustment using the final popPK model was assessed by a simulation study. The ratio of the first trough measurement within the therapeutic range of 3-8 ng/mL increased from 69.8% in the original dose to 87.9% in the individual dose calculated by the final PopPK model. The tacrolimus C/D ratio before initiating everolimus therapy and the hematocrit value were useful to estimate the initial dose of everolimus and can improve the safety and effectiveness of immunosuppressive therapy involving everolimus.

Predicting factors for omitting beta-blockers in patients with tachycardia-induced cardiomyopathy after successful catheter ablation for atrial fibrillation.

Tachycardia induces a reduction in the left ventricular ejection fraction (LVEF), which is defined as tachycardia-induced cardiomyopathy (TIC). Conversion to and maintenance of sinus rhythm by catheter ablation can improve LVEF in patients with TIC due to atrial fibrillation (AF). Beta-blockers are mandatory for the treatment of heart failure with reduced LVEF(HFrEF), but the necessity of beta-blockers in TIC patients even after catheter ablation remains unclear. We examined the effect of beta-blockers on cardiac function in TIC patients after catheter ablation. We retrospectively analyzed 124 patients with a history of heart failure and an LVEF of ≤ 50% who underwent catheter ablation for AF. TIC was defined as a ≥ 10% improvement in the baseline LVEF and an improvement to an LVEF of ≥ 50% at 6 months after ablation. Patients with other cardiomyopathy diagnosed before the ablation were excluded. LVEF was significantly increased with the reductions of the left ventricular and left atrial volumes at the 6-month follow-up in all 80 patients with TIC. No beta-blockers were prescribed during the post-ablation follow-up in 21 patients with TIC. The absolute values of and changes in the echocardiographic parameters between before and after ablation were not significantly different between patients with and without beta-blockers after the ablation. A simple score using the history of hospitalization for heart failure and use of beta-blockers or diuretics prior to ablation was useful in identifying TIC patients who did not need prescription of beta-blockers after catheter ablation. LVEF similarly improved in both patients with and without prescription of beta-blockers after the ablation. Beta-blockers may not need to be prescribed after successful catheter ablation for AF in LVEF of ≤ 50% patients without other cause of cardiomyopathy diagnosed before the ablation, a history of hospitalization for heart failure and prescription of beta-blockers and diuretics before the ablation.

Electrochemical Analysis for Total Alkalinity of Water by the Measurement of Cathodic Prepeak of Quinone Caused by Surplus Acid.

In this study, an electrochemical analysis, coupled with the concept of back neutralization titration and the voltammetric determination of surplus acid, is proposed for determining the total alkalinity of water samples. When linear sweep voltammetry of 3,5-di-tert-butyl-1,2-benzoquinone (DBBQ) with H2SO4 in a water and ethanol (44 : 56, v/v) mixture was carried out using a bare glassy carbon working electrode, a cathodic prepeak of DBBQ caused by H2SO4 was observed on the voltammogram at a more positive potential than when compared with the original cathodic peak of DBBQ. When similar voltammetry was carried out in the presence of Na2CO3 and H2SO4, the cathodic prepeak height of DBBQ was decreased with an increase in the Na2CO3 concentration. The decrease of the cathodic prepeak height of DBBQ was found to be linearly related to the Na2CO3 concentration ranging from 0.025 to 2.5 mM (r2 = 0.998). The total equivalent concentrations of inorganic bases in samples of mineral water and tap water were determined, and then the results were converted to the total alkalinities of the water samples (mg/L CaCO3). The total alkalinities of the water samples determined by the present electrochemical analysis were essentially the same compared with those by the neutralization titration method. From these results, we were able to demonstrate that the present electrochemical analysis with accuracy and precision could be applied to determine the total alkalinity, which is one of the indicators to examine water quality. The present electrochemical analysis would contribute to achieving the sustainable development goals (SDGs) of #6 and #14.

Two-Year Clinical Outcome of MitraClip Transcatheter Edge-to-Edge Repair From the J-MITRA Registry Data.

BACKGROUND: The introduction of transcatheter edge-to-edge repair for moderate-to-severe or severe mitral regurgitation (MR) utilizing the MitraClip system became reimbursed and clinically accessible in Japan in April 2018. This study presents the 2-year clinical outcomes of all consecutively treated patients who underwent MitraClip implantation in Japan and were prospectively enrolled in the Japanese Circulation Society-oriented J-MITRA registry.Methods and Results: Analysis encompassed 2,739 consecutive patients enrolled in the J-MITRA registry with informed consent (mean age: 78.3±9.6 years, 1,550 males, STS risk score 11.7±8.9), comprising 1,999 cases of functional MR, 644 of degenerative MR and 96 in a mixed group (DMR and FMR). The acute procedure success rate was 88.9%. After MitraClip implantation, >80% exhibited an MR grade ≤2+ and the trend was sustained over the 2 years. Within this observation period, the mortality rate was 19.3% and the rate of heart failure readmissions was 20.6%. The primary composite endpoint, inclusive of cardiovascular death and heart failure readmission, was significantly higher in patients with functional MR than in with degenerative MR (32.0% vs. 17.5%, P<0.001). CONCLUSIONS: The 2-year clinical outcomes after MitraClip implantation were deduced from comprehensive data within an all-Japan registry.

Double Microballoon-occluded Ethanol Embolization for Pelvic Arteriovenous Malformation: A Case Report.

A 40-year-old man was incidentally found to have right-sided pelvic arteriovenous malformation (AVM) with an aneurysmal dominant outflow vein (DOV). The AVM had two main feeding arteries forming a cluster of fine vessels shunt to the DOV. As transvenous approach was impossible due to anatomical difficulty, transarterial ethanol embolization was performed under simultaneous double microballoon occlusion of the two feeding arteries in combination with protective coil embolization of the prostatic branches. Ethanol (13 mL) was intermittently injected from both microballoon catheters until the AV shunt was completely occluded. At 1-year follow-up, contrast-enhanced CT revealed shrinkage of the thrombosed DOV without any symptom. Our case demonstrated the usefulness of simultaneous double microballoon-occluded ethanol embolization for treating a localized pelvic AVM with a few feeding arteries.

Effect of early dose reduction of osimertinib on efficacy in the first-line treatment for EGFR-mutated non-small cell lung cancer.

Osimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC.

Predictor of A4 amplitude using preprocedural electrocardiography in patients with leadless pacemakers.

BACKGROUND: Based on historical studies of leadless pacemakers (LPs), high atrioventricular synchrony (AVS) with mechanical sensing-based VDD pacing is largely influenced by A4 amplitude. A limited study investigated the predictors of A4 amplitude using clinical and echocardiographic parameters. OBJECTIVE: The purpose of this study was to investigate the predictors of A4 amplitude preoperatively to select patients who could benefit the most from AVS among patients with VDD LPs (Micra-AV, Medtronic). METHODS: Data from patients who received Micra-AV implantations from November 2021 to August 2023 at Tottori University Hospital were analyzed. Twelve-lead electrocardiography and transthoracic echocardiography were performed before the Micra-AV implantations. To assess the electrical indices associated with the A4 signal, electrocardiographic morphologic P-wave parameters were analyzed, including P-wave duration, P-wave amplitude, maximum deflection index (MDI), and P-wave dispersion. RESULTS: A total of 50 patients who underwent Micra-AV implantations (median age 84 years; 64% male) were included and divided into 2 groups based on the median value of A4 amplitude, the high-A4 group (A4 amplitude >2.5 m/s2; n = 26), and low-A4 group (A4 amplitude ≤2.5 m/s2; n = 24). There was a significant difference between the high-A4 and low-A4 groups with regard to left ventricular ejection fraction (P = .01), P-wave dispersion (P = .01), and MDI (P <.001). Multivariate logistic analysis revealed that lower MDI was an independent predictor of high A4-amplitude (odds ratio 0.78; 95% confidence interval 0.67-0.92; P = 0.003). CONCLUSION: Preoperative electrocardiographic evaluations of P-wave morphology may be useful for predicting A4 amplitude. MDI was the only independent A4 amplitude predictor that seemed promising for selecting Micra-AV patients.

The Efficacy of Bepotastine Besilate Compared With Hydroxyzine Pamoate for Preventing Infusion Reactions to the First Dose of Rituximab in Patients With Non-Hodgkin Lymphoma: Protocol for a Phase II, Double-Blind, Multicenter Randomized Trial.

BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody, can cause infusion reactions (IRs), especially during the initial rituximab infusion therapy. Generally, patients are administered a histamine H1-receptor antagonist before the rituximab infusion, along with an antipyretic analgesic, to prevent or reduce IRs. Multiple retrospective case-control studies indicate that the second generation of histamine H1-receptor antagonists might be more effective than the first generation in suppressing IRs caused by the rituximab infusion. OBJECTIVE: This study aimed to assess the efficacy of first- and second-generation histamine H1-receptor antagonists for preventing IRs resulting from the initial infusion of rituximab in patients diagnosed with non-Hodgkin lymphoma. METHODS: This is a phase II, double-blind, active-controlled randomized trial. It will be a multicenter study conducted across 3 facilities that aims to enroll a total of 40 patients diagnosed with non-Hodgkin lymphoma who will receive their initial rituximab infusion. Participating patients will be administered hydroxyzine pamoate or bepotastine besilate, representing first- or second-generation histamine H1-receptor antagonists, respectively. This will be combined with 400-mg acetaminophen tablets taken approximately 30 minutes before the first infusion of rituximab. The primary end point of this trial is to assess severe IRs, equivalent to grade 2 or higher as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, that occur within a 4-hour period after the initiation of rituximab infusion. The secondary end points include assessing the severity of the initial IR, the maximum severity of the IR, and the duration between rituximab infusion initiation and the onset of the first IR within a 4-hour period. Additionally, the trial will evaluate histamine H1-receptor antagonist-induced drowsiness using the visual analogue scale, with each patient providing their individual response. RESULTS: This study began with patient recruitment in April 2023, with 17 participants enrolled as of November 12, 2023. The anticipated study completion is set for February 2026. CONCLUSIONS: This study is the first randomized controlled trial comparing the effects of oral first- and second-generation histamine H1-receptor antagonists in preventing IRs induced by the initial administration of rituximab. The findings from this study hold the potential to establish the rationale for a phase III study aimed at determining the standard premedication protocol for rituximab infusion. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051220169; https://jrct.niph.go.jp/latest-detail/jRCTs051220169. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54882.

Mitochondrial Responses to Sublethal Doxorubicin in H9c2 Cardiomyocytes: The Role of Phosphorylated CaMKII.

Background: Doxorubicin (Dox) is effective against different types of cancers, but it poses cardiotoxic side effects, frequently resulting in irreversible heart failure. However, the complexities surrounding this cardiotoxicity, especially at sublethal dosages, remain to be fully elucidated. We investigated early cellular disruptions in response to sublethal Dox, with a specific emphasis on the role of phosphorylated calcium/calmodulin-dependent protein kinase II (CaMKII) in initiating mitochondrial dysfunction. Methods: This study utilized the H9c2 cardiomyocyte model to identify a sublethal concentration of Dox and investigate its impact on mitochondrial health using markers such as mitochondrial membrane potential (MMP), mitophagy initiation, and mitochondrial calcium dynamics. We examined the roles of and interactions between CaMKII, dynamin-related protein 1 (Drp1), and the mitochondrial calcium uniporter (MCU) in Dox-induced mitochondrial disruption using specific inhibitors, such as KN-93, Mdivi-1, and Ru360, respectively. Results: Exposure to a sublethal dose of Dox reduced the MMP red-to-green fluorescence ratio in H9c2 cells by 40.6% compared with vehicle, and increased the proportion of cells undergoing mitophagy from negligible levels compared with vehicle to 62.2%. Mitochondrial calcium levels also increased by 8.7-fold compared with the vehicle group. Notably, the activation of CaMKII, particularly its phosphorylated form, was pivotal in driving these mitochondrial changes, as inhibition using KN-93 restored MMP and decreased mitophagy. However, inhibition of Drp1 and MCU functions had a limited impact on the observed mitochondrial disruptions. Conclusion: Sublethal administration of Dox is closely linked to CaMKII activation through phosphorylation, emphasizing its pivotal role in early mitochondrial disruption. These findings present a promising direction for developing therapeutic strategies that may alleviate the cardiotoxic effects of Dox, potentially increasing its clinical efficacy.

Factors affecting the willingness of nursing care staffs for cooperation with heart failure care and the role of internet video education.

Background: With the aging of heart failure (HF) patients, collaboration between medical and nursing care facilities is essential for HF care. The aims of this study were: (1) to identify the factors that affect willingness of nursing care staffs to cooperate with HF care; (2) to test whether the internet video education is useful in improving their willingness to collaborate. Methods: A web-based questionnaire was e-mailed to 417 registered medical corporations that operated nursing care facilities in the prefecture where the authors work. Medical and care staff working at each facility were asked their willingness to cooperate with HF care and their problems about collaboration. Machine learning analysis was used to assess the factors associated with unwillingness to cooperate. After watching a 6-min YouTube video explaining HF and community collaboration, we reaffirmed their willingness to cooperate. Results: We received responses from 76 medical and care staff members. Before watching the video, 32.9% of participants stated that they were unwilling to cooperate with HF care. Machine learning analysis showed that job types, perceived problems of collaboration, and low opportunities to learn about HF were associated with unwillingness to cooperation. After watching the video, we observed an increase from 67.1% to 80.3% (p < 0.05) of participants willing to cooperate with HF care. Conclusions: Job types, perceived problems of collaboration, and low opportunities to learn about HF are associated with unwillingness of nursing care staff for HF care. Internet videos are potential learning tool that can easily promote community collaboration for HF.

Imaging features of mucinous carcinoma arising from mature teratoma showing cytokeratin 7+ and cytokeratin 20+ expression profile: A case report.

Ovarian mature teratomas are benign, but malignant transformation can occur infrequently, especially in women of advanced age. The tissue that undergoes malignant change is mostly squamous cell carcinoma, although adenocarcinoma has been reported in a small number of cases. The immunostaining results of adenocarcinoma usually show a cytokeratin (CK)7-/CK20+ expression profile, corresponding to lower gastrointestinal tract origin. In this report, we describe a case of mucinous carcinoma arising from an ovarian mature teratoma showing a CK7+/CK20+ profile and discuss its imaging features. A 40-year-old woman presented to her primary care physician with abdominal distension and poor oral intake, and she was referred to our hospital. She had been diagnosed with an ovarian mature teratoma at our institution 3 years earlier. At the current presentation, pelvic magnetic resonance imaging showed a large multilocular cystic mass with adipose tissue extending into the upper abdomen. Densely packed cysts were observed inside the mass, which showed weak contrast enhancement on contrast-enhanced imaging and a mildly high signal on diffusion-weighted imaging. A portion of the cysts also showed abnormal 18F-fluorodeoxyglucose uptake (maximum standardized uptake value, 13.2) on positron emission tomography/computed tomography. The patient was subsequently diagnosed with mucinous carcinoma showing a CK7+/CK20+ profile arising from a mature teratoma by pathologic examination. This mucinous carcinoma arising from a mature teratoma showed a CK7+/CK20+ profile and took the form of densely packed multilocular cysts. In this respect, it was similar to primary ovarian epithelial mucinous carcinoma on both magnetic resonance imaging and pathologic examination despite showing a much higher maximum standardized uptake value than that of primary ovarian mucinous carcinoma. When a large ovarian teratoma contains a large multilocular cyst, the presence of densely packed multilocular cysts should not be missed even in a mass without solid components. Clinicians should consider the possibility of mucinous carcinoma showing a CK7+/CK20+ profile arising from a mature teratoma in such cases.

Luteolin Protects Against 6-Hydoroxydopamine-Induced Cell Death via an Upregulation of HRD1 and SEL1L.

Parkinson's Disease (PD) is caused by many factors and endoplasmic reticulum (ER) stress is considered as one of the responsible factors for it. ER stress induces the activation of the ubiquitin-proteasome system to degrade unfolded proteins and suppress cell death. The ubiquitin ligase 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation 1 (HRD1) and its stabilizing molecule, the suppressor/enhancer lin-12-like (SEL1L), can suppress the ER stress via the ubiquitin-proteasome system, and that HRD1 can also suppress cell death in familial and nonfamilial PD models. These findings indicate that HRD1 and SEL1L might be key proteins for the treatment of PD. Our study aimed to identify the compounds with the effects of upregulating the HRD1 expression and suppressing neuronal cell death in a 6-hydroxydopamine (6-OHDA)-induced cellular PD model. Our screening by the Drug Gene Budger, a drug repositioning tool, identified luteolin as a candidate compound for the desired modulation of the HRD1 expression. Subsequently, we confirmed that low concentrations of luteolin did not show cytotoxicity in SH-SY5Y cells, and used these low concentrations in the subsequent experiments. Next, we demonsrated that luteolin increased HRD1 and SEL1L mRNA levels and protein expressions. Furthermore, luteolin inhibited 6-OHDA-induced cell death and suppressed ER stress response caused by exposure to 6-OHDA. Finally, luteolin did not reppress 6-OHDA-induced cell death when expression of HRD1 or SEL1L was suppressed by RNA interference. These findings suggest that luteolin might be a novel therapeutic agent for PD due to its ability to suppress ER stress through the activation of HRD1 and SEL1L.

Uterine myxoid leiomyosarcoma initially showing low signal intensity on T2 weighted images: A case report.

In the few articles describing MRI findings of myxoid leiomyosarcoma (MLMS), high signal intensity (SI) on T2-weighted images (T2WI) due to myxoid change was believed to be one of the common features. However, we encountered an MLMS with low SI similar to uterine myometrium on T2WI that subsequently grew with extremely edematous change even after 3 cycles of gonadotropin-releasing hormone agonist (GnRHa) treatment. Here we present this atypical MLMS case with radiologic-pathologic correlation. The patient was a 46-year-old woman with a chief complaint of low abdominal pain. The tumor was a pedunculated mass arising from the right anterior wall of the uterus that included a low-SI tumor-like component that partially transitioned into a peripheral high-SI component on T2WI and was diagnosed as hydropic leiomyoma. After 3 cycles of GnRHa therapy, the tumor size increased along with the size of the peripheral high-SI component on T2WI, while the size of the low-SI tumor-like component decreased. A small markedly low-SI area on both T1 and T2WI and a subtle high-SI area on fat-saturated T1WI indicating hemorrhage were present within the tumor. Pathologically, not only the peripheral high-SI component but also the low-SI tumor-like component on T2WI corresponded to MLMS, and the high-SI component was associated mainly with edematous change rather than myxoid change. MLMS may initially show low SI on T2WI and change to high SI mainly due to edematous change with rapid growth. Intratumoral hemorrhage might be the only key feature to differentiates MLMS from hydropic leiomyoma.

Fasting hepatic insulin clearance reflects postprandial hepatic insulin clearance: a brief report.

BACKGROUND: Hepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes mellitus (T2DM). HIC was reported to decrease in patients with type 2 diabetes and metabolic syndrome. HIC is originally calculated by post-load insulin and C-peptide from the oral glucose tolerance test (OGTT). However, OGTT or meal tolerance tests are a burden for patients, and OGTT is not suitable for overt diabetes due to the risk of hyperglycemia. If we can calculate the HIC from the fasting state, it is preferable. We hypothesized that fasting HIC correlates with postprandial HIC in both participants with T2DM and without diabetes. We investigated whether fasting HIC correlates with postprandial HIC in overt T2DM and nondiabetes subjects (non-DM) evaluated by using glucose clamp and meal load. METHODS: We performed a meal tolerance test and hyperinsulinemic-euglycemic clamp in 70 subjects, 31 patients with T2DM and 39 non-DM subjects. We calculated the postprandial C-peptide AUC-to-insulin AUC ratio as the postprandial HIC and the fasting C-peptide-to-insulin ratio as the fasting HIC. We also calculated whole-body insulin clearance from the glucose clamp test. RESULTS: The fasting HIC significantly correlated with postprandial HIC in T2DM (r_S = 0.82, P < 0.001). Nondiabetes subjects also showed a significant correlation between fasting and postprandial HIC (r_S = 0.71, P < 0.001). Fasting HIC in T2DM was correlated with BMI, HbA1c, gamma-glutamyl transpeptidase, HOMA-IR, HOMA-beta, M/I, and whole-body insulin clearance. Fasting HIC in nondiabetes subjects was correlated with HOMA-IR and HOMA-beta. CONCLUSIONS: These results suggest that fasting HIC is strongly correlated with postprandial HIC in both overt T2DM and non-DM patients, as evaluated by the meal test and glucose clamp method. Fasting HIC could be a convenient marker of HIC.

[Molecular Mechanism-based Prediction of Interstitial Lung Disease Development Causedby Molecular Targeted Drugs: Association between Signal Transducer and Activator of Transcription 3 and Mammalian Target of Rapamycin inhibitor-induced Interstitial Lung Disease].

Interstitial lung disease (ILD) is a serious adverse event common to many molecular targeted anticancer drugs. The development of ILD significantly reduces the QOL of patients and results in treatment discontinuation. Because the development of ILD is also associated with therapeutic efficacy, the establishment of prediction strategies for ILD is important. We have focused on signal transducer and activator of transcription 3 (STAT3) as an important mechanistic factor in ILD induced by molecular targeted drugs. Our study aimed to establish mechanism-based ILD prediction strategies; therefore, we investigated the hypothesis that a genetic polymorphism in STAT3 is a predictive factor of the incidence of ILD induced by mammalian target of rapamycin (mTOR) inhibitors, a class of molecular targeted drugs associated with a higher incidence of ILD. Our clinical study clearly demonstrated that the rate of ILD induced by mTOR inhibitors was significantly higher in patients with the G allele homozygous genotype of STAT3 -1697C>G compared with those with other genotypes. The cumulative incidence of ILD in patients with the G allele homozygous genotype was significantly higher compared with that in patients carrying other genotypes. Furthermore, our in vitro study indicated that the epithelial-to-mesenchymal transition (EMT), a pre-process of tissue fibrosis, was induced by an mTOR inhibitor in lung alveolar epithelial cell lines carrying the G allele homozygous genotype which was associated with a higher risk of ILD. Our study provided a novel predictive strategy for the development of ILD induced by molecular targeted drugs.

Efficacy and Safety of Sacubitril/Valsartan in Japanese Patients With Heart Failure According to Baseline Systolic Blood Pressure　- Results From a Subgroup Analysis of the PARALLEL-HF Study.

BACKGROUND: Lower systolic blood pressure (SBP) is known to be associated with poor prognosis in heart failure (HF). We evaluated the efficacy and safety of sacubitril/valsartan according to baseline SBP tertiles in Japanese patients from the PARALLEL-HF study.Methods and Results: In all, 223 patients were stratified into tertiles according to baseline SBP (≤114 mmHg: n=75; >114 and ≤130 mmHg: n=76; and >130 mmHg: n=72). Patients with lower SBP (≤114 mmHg) had the highest median N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations at baseline (P=0.0184). No significant difference was observed between sacubitril/valsartan and enalapril for the composite outcome of cardiovascular death and HF hospitalization across SBP tertiles (P-interaction=0.2682). Although the P-interaction value was not significant (0.2106), a greater reduction in NT-proBNP with sacubitril/valsartan compared with enalapril was observed in patients with SBP >130 mmHg (P=0.0076). The incidence of hypotension-related events and reduction or discontinuation of treatment due to hypotension-related events was higher in the lower SBP subgroup, and these events were more frequent in the sacubitril/valsartan than enalapril group. CONCLUSIONS: The efficacy of sacubitril/valsartan compared with enalapril was consistent across baseline SBP tertiles in Japanese patients from the PARALLEL-HF study. Hypotension-related events were more common in patients treated with sacubitril/valsartan with lower SBP.