Effectiveness of DialBetesPlus, a self-management support system for diabetic kidney disease: Randomized controlled trial.

We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group's change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: -32.3% [95% CI: -49.2%, -9.8%] between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.

Lipoprotein Apheresis Alleviates Treatment-Resistant Peripheral Artery Disease Despite the Normal Range of Atherogenic Lipoproteins: The LETS-PAD Study.

AIM: Peripheral artery disease (PAD) severely impairs patient prognosis and quality of life (QOL). Although lipoprotein apheresis (LA) has been applied to patients with PAD and elevated serum atherogenic lipoproteins, we hypothesized that LA can be effective for treating PAD even in patients with controlled serum lipoproteins through pleiotropic anti-atherosclerotic effects beyond lipoprotein removal. This study aimed to evaluate the efficacy of LA in patients with treatment-resistant PAD and controlled serum lipoproteins focusing on QOL. METHODS: In a single-arm prospective study, 30 patients with refractory PAD who had controlled serum lipoproteins underwent sequential LA sessions using dextran sulfate adsorption columns, aiming to complete 10 sessions. The ankle-brachial pressure index (ABI) and vascular QOL (VascuQOL) score were evaluated as the primary outcomes. Secondary outcomes included reactive hyperemia index (RHI) and biological antioxidant potential (BAP) as an endothelial function test and serum antioxidative-capacity evaluation, respectively. RESULTS: ABI significantly increased after LA sessions (pre-treatment 0.60±0.09 vs. post-treatment 0.65±0.13, p=0.023). Total VascuQOL score (3.7±1.1 vs 4.6±1.1, p＜0.001) and RHI (1.70±0.74 vs 2.34±1.76, p=0.023) significantly improved after the LA sessions. BAP tended to increase after the LA sessions, and the change reached statistical significance 3 months after treatment. CONCLUSION: ABI and QOL improved after a series of LA sessions in conventional treatment-resistant PAD patients with controlled serum lipoprotein levels. Increased antioxidative capacity and ameliorated endothelial function were observed after the LA treatment.

Analysis of clinical factors associated with Kampo formula-induced pseudoaldosteronism based on self-reported information from the Japanese Adverse Drug Event Report database.

Drug-induced pseudoaldosteronism is a typical adverse effect of Kampo formulas. Previous research described the potential risks of Kampo formula-linked pseudoaldosteronism. However, few studies assessed the risk factors using a real-world database and a data-mining approach. Using the Japanese Adverse Drug Event Report database, we extracted pseudoaldosteronism reports for 148 Kampo formulas covered by Japanese national health insurance. Adverse events were decided according to the preferred terminology of the Medical Dictionary for Regulatory Activities/Japanese version 25.1. We calculated reporting odds ratio (RORs) and identified Kampo formulas as suspected causes of pseudoaldosteronism. Moreover, we evaluated clinical factors associated with Kampo formula-induced pseudoaldosteronism via logistic regression. From April 2004 to November 2022, 6334 adverse events related to the Kampo formulas were reported. We selected 2471 reports containing complete clinical data, including 210 reports on pseudoaldosteronism. In the pseudoaldosteronism group, 69.0% of patients were female, and 85.2% were ≥70 years old. The formulas most commonly associated with pseudoaldosteronism were Shakuyakukanzoto, Yokukansan, and Ryokeijutsukanto (ROR [95% confidence interval {CI}] = 18.3 [13.0-25.9], 8.1 [5.4-12.0], and 5.5 [1.4-21.9], respectively). Logistic analysis identified female sex (odds ratio [OR] [95% CI] = 1.7 [1.2-2.6]; P = 0.006), older age (≥70, 5.0 [3.2-7.8]; P < 0.001), low body weight (<50 kg, 2.2 [1.5-3.2]; P < 0.001), diuretics usage (2.1 [1.3-4.8]; P = 0.004), hypertension (1.6 [1.1-2.4]; P = 0.014), and dementia (7.0 [4.2-11.6]; P < 0.001) as pseudoaldosteronism-related factors. Additionally, the daily Glycyrrhiza dose (OR = 2.1 [1.9-2.3]; P < 0.001) and duration of administration (>14 days, OR = 2.8 [1.7-4.5]; P < 0.001) were associated with adverse events. We did not observe an interaction between aging and hypertension. Careful follow-up is warranted during long-term Glycyrrhiza-containing Kampo formula use in patients with multiple clinical factors for pseudoaldosteronism.

The Use of Information and Communication Technology-Based Self-management System DialBeticsLite in Treating Abdominal Obesity in Japanese Office Workers: Prospective Single-Arm Pilot Intervention Study.

BACKGROUND: Making lifestyle changes is an essential element of abdominal obesity (AO) reduction. To support lifestyle modification and self-management, we developed an information and communication technology-based self-management system-DialBeticsLite-with a fully automated dietary evaluation function for the treatment of AO. OBJECTIVE: The objective of this study was to evaluate the preliminary efficacy and feasibility of DialBeticsLite among Japanese office workers with AO. METHODS: A 2- to 3-month prospective single-arm pilot intervention study was designed to assess the effects of the intervention using DialBeticsLite. The information and communication technology system was composed of 4 modules: data transmission (body weight, blood pressure, blood glucose, and pedometer count); data evaluation; exercise input; and food recording and dietary evaluation. Eligible participants were workers who were aged ≥20 years and with AO (waist circumference ≥85 cm for men and ≥90 cm for women). Physical parameters, blood tests, nutritional intake, and self-care behavior were compared at baseline and after the intervention. RESULTS: A total of 48 participants provided completed data for analysis, which yielded a study retention rate of 100%. The average age was 46.8 (SD 6.8) years, and 92% (44/48) of participants were male. The overall average measurement rate of DialBeticsLite, calculated by dividing the number of days with at least one measurement by the number of days of the intervention, was 98.6% (SD 3.4%). In total, 85% (41/48) of the participants reported that their participation in the study helped them to improve their lifestyle. BMI, waist circumference, and visceral fat area decreased significantly after the intervention (P<.001). In addition, the daily calorie intake reduced significantly (P=.02). There was a significant improvement in self-care behavior in terms of exercise and diet (P=.001). CONCLUSIONS: Using DialBeticsLite was shown to be a feasible and potentially effective method for reducing AO by providing users with a motivational framework to evaluate their lifestyle behaviors.

Japanese traditional Kampo medicine bofutsushosan improves body mass index in participants with obesity: A systematic review and meta-analysis.

BACKGROUND: The number of people with obesity is rapidly increasing worldwide. Since obesity is a critical risk factor for cardiovascular diseases and mortality, the management of obesity is an urgent issue. However, anti-obesity drugs are insufficient in current clinical settings. Bofutsushosan (BTS, Fang-Feng-Tong-Sheng-San in China) is a traditional Japanese Kampo formula for patients with obesity. Recent basic studies have indicated that BTS potentially improves the pathophysiology of obesity. However, it is still unknown whether BTS clinically reduces body mass index (BMI) in patients with obesity. METHODS: We searched electronic databases, including the Medline, EMBASE, Cochrane Library, and Japanese/Chinese/Korean databases, on June 15, 2021. We conducted a meta-analysis of randomized controlled trials to evaluate the effects of BTS on BMI, waist circumference, glycolipid metabolism, and blood pressure in participants with obesity. The primary outcome was change in BMI. RESULTS: We included seven studies and 679 participants (351 in the BTS group and 328 in the control group). In participants with obesity, BTS significantly reduced BMI relative to controls (mean difference, MD [95% confidence interval]: -0.52 kg/m2 [-0.86, -0.18], P = 0.003). There was no significant difference in waist circumference, glycolipid parameters, or blood pressure. Sensitivity analyses showed robust outcomes for the primary endpoint, although the heterogeneity was considerable. Moreover, no serious adverse events were observed in the BTS group. CONCLUSION: BTS showed a potential benefit in safely and tolerably improving BMI in participants with obesity.

Clinical significance of a novel reticulocyte-based erythropoietin resistance index in HD patients: A retrospective study.

INTRODUCTION: The erythropoietin resistance index (ERI) is an indicator of erythropoiesis-stimulating agent (ESA) responsiveness and is typically calculated using Hb. However, Hb does not directly reflect ESA-induced erythropoiesis because of its long-term nature. We thus designed a novel ERI calculated with reticulocyte Hb (RetHb), a real-time index, and investigated its association with mortality in HD patients. METHODS: We calculated the ERI using the change in RetHb before and after ESA administration (ERIΔRetHb ) and retrospectively analyzed its association with 3-year all-cause mortality using Kaplan-Meier survival curves and Cox regression analyses. RESULTS: A total of 102 patients were included. Patients with the highest ERIΔRetHb had the worst prognosis according to the Kaplan-Meier survival curves (Log-rank p = 0.02). Multivariate Cox regression analysis showed that the ERIΔRetHb was significantly and independently associated with all-cause mortality (hazard ratio: 9.82, 95% CI [1.50, 64.41], p = 0.02). CONCLUSION: The ERIΔRetHb was significantly and independently associated with all-cause mortality in HD patients.

Comparison of effects of SGLT-2 inhibitors and GLP-1 receptor agonists on cardiovascular and renal outcomes in type 2 diabetes mellitus patients with/without albuminuria: A systematic review and network meta-analysis.

AIMS: It remains unclear which sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are most effective for preventing cardiovascular and renal events in type 2 diabetes mellitus (T2DM) patients, depending on the presence of albuminuria. We conducted a network meta-analysis to compare the efficacy of these two drug classes in T2DM patients with/without albuminuria. METHODS: We searched the Medline, EMBASE, Cochrane Library databases, and gray literature up to April 20, 2021. We included randomized controlled trials that reported the risk of major adverse cardiovascular events (MACE) and composite of renal outcomes in T2DM. RESULTS: A total of nine studies (81,206 patients) were included. In patients with/without albuminuria, SGLT-2 inhibitors did not significantly reduce the risk of MACE compared with GLP-1 RAs (risk ratio [RR] [95% confidence interval]; 0.96 [0.82-1.12] and 0.94 [0.81-1.10], respectively). In contrast, compared with GLP-1 RAs, SGLT-2 inhibitors were associated with significantly lower renal risk in both patients with/without albuminuria (RR [95% CI]; 0.75 [0.63-0.89] and 0.59 [0.44-0.79], respectively). CONCLUSIONS: SGLT-2 inhibitors may be superior to GLP-1 RAs for renal outcomes in T2DM patients with/without albuminuria, although there was no difference in the risk of MACE.

Efficacy of the Self-management Support System DialBetesPlus for Diabetic Kidney Disease: Protocol for a Randomized Controlled Trial.

BACKGROUND: Diabetic kidney disease (DKD) is one of the main complications of type 2 diabetes mellitus (T2DM). DKD is a known risk factor for end-stage renal disease, cardiovascular disease, and all-cause death. Effective intervention for early-stage DKD is vital to slowing down the progression of kidney disease and improve prognoses. Mobile health (mHealth) is reportedly effective in supporting patients' self-care and improving glycemic control, but the impact of mHealth on DKD has yet to be shown. OBJECTIVE: The purpose of this study is to evaluate the efficacy of standard therapy with the addition of a self-management support system, DialBetesPlus, in patients with DKD and microalbuminuria. METHODS: This study is a prospective, randomized, open-label, multicenter clinical trial. The target population consists of 160 patients diagnosed with T2DM accompanied by microalbuminuria. We randomly assigned the patients to 2 groups-the intervention group using DialBetesPlus in addition to conventional therapy and the control group using conventional therapy alone. DialBetesPlus is a smartphone application that supports patients' self-management of T2DM. The study period was 12 months, with a follow-up survey at 18 months. The primary outcome was a change in albuminuria levels at 12 months. Secondary outcomes included changes in physical parameters, blood test results (glycemic control, renal function, and lipid metabolism), lifestyle habits, self-management scores, medication therapy, and quality of life. RESULTS: The study was approved in April 2018. We began recruiting patients in July 2018 and completed recruiting in August 2019. The final 18-month follow-up was conducted in March 2021. We recruited 159 patients and randomly allocated 70 into the intervention group and 61 into the control group, with 28 exclusions due to withdrawal of consent, refusal to continue, or ineligibility. The first results are expected to be available in 2021. CONCLUSIONS: This is the first randomized controlled trial assessing the efficacy of mHealth on early-stage DKD. We expect that albuminuria levels will decrease significantly in the intervention group due to improved glycemic control with ameliorated self-care behaviors. TRIAL REGISTRATION: UMIN-CTR UMIN000033261; https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000037924. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31061.

Potential effective treatment of shortening continuous erythropoietin receptor activator treatment interval combined with iron supplementation in hemodialysis patients.

Our previous randomized controlled trial comparing the total dose of weekly versus biweekly continuous erythropoietin receptor activator (CERA) therapy to maintain optimal hemoglobin (Hb) levels showed no significant differences between the two therapies. This post-hoc analysis assessed whether the total dose of weekly versus biweekly CERA therapy to maintain Hb levels among HD patients differed among groups with or without iron supplementation. Of 107 patients, 40 received intravenous iron supplementation due to iron deficiency (iron group) and 67 did not (non-iron group). In the iron group, the weekly therapy tended to require a lower total CERA dose compared with the biweekly therapy (274 ± 274 vs 381 ± 223 µg/12 weeks, P = 0.051). Changes in circulating hepcidin levels, a negative regulator of intestinal iron uptake, after 2 weeks of CERA treatment were significantly lower in the weekly therapy compared with the biweekly therapy (-4.2 ± 6.3 vs 11.1 ± 7.3 ng/mL, P = 0.015). In the non-iron group, there were no significant differences in total CERA dose or changes in hepcidin levels between the two therapies. Shortening the CERA treatment interval combined with iron supplementation may lead to the more efficient treatment of HD patients with iron deficiency.

Systematic review and meta-analysis for prevention of cardiovascular complications using GLP-1 receptor agonists and SGLT-2 inhibitors in obese diabetic patients.

Patients with type 2 diabetes mellitus (T2DM) and obesity are at high risk of developing cardiovascular disease (CVD). Both glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter (SGLT-2) inhibitors have been shown to prevent CVD in T2DM patients. Additionally, the two drugs reduce body mass. However, it is unknown which drug is more effective at reducing the risk of CVD in such patients. We searched Medline, EMBASE, and Cochrane Library records to February 20, 2021 and performed a network meta-analysis to compare the efficacy with which the drugs reduced the risk of major adverse cardiovascular events (MACE). We included 102,728 patients in 12 studies containing data of obesity subgroup analyses. In T2DM patients with obesity, GLP-1 RAs significantly reduced the risk of MACE versus placebo (relative risk, RR [95% confidence interval, CI]: 0.88 [0.81-0.96]), whereas SGLT-2 inhibitors showed a tendency (RR [95% CI]: 0.91 [0.83-1.00]). In an indirect comparison, GLP-1 RAs were not associated with a significant difference in MACE compared with SGLT-2 inhibitors (RR [95% CI]: 0.97 [0.85-1.09]). Thus, GLP-1 RAs are effective at preventing MACE than placebo in T2DM patients with obesity, although further studies are warranted to conclude their superiority to SGLT-2 inhibitors.

Comparison of the effects of weekly and biweekly intravenous CERA administration on erythropoiesis: A randomized controlled trial.

Although continuous erythropoietin receptor activators (CERAs) are widely used erythropoiesis-stimulating agents for correcting renal anemia in patients undergoing hemodialysis (HD), few reports have examined weekly CERA administration. In this randomized controlled trial, we compared the efficacy and changes in the parameters of iron metabolism and erythropoiesis between weekly and biweekly CERA administration. In total, 120 patients undergoing maintenance HD were randomized to the weekly or biweekly group. The primary end point was the total CERA dose needed to maintain the target hemoglobin (Hb) levels during a 12-week evaluation period. There was no significant difference in the total dose between the weekly and biweekly groups (median 175.0 [interquartile range (IQR) 93.8-337.5] µg/12 weeks vs. 300.0 [IQR 125.0-375.0] µg/12 weeks, P = .18). The mean Hb levels during the evaluation period were 10.9 ± 0.8 g/dL in the weekly group and 10.7 ± 0.8 g/dL in the biweekly group (P = .25). Weekly CERA administration was well tolerated. Weekly CERA administration similarly managed anemia as biweekly administration in patients undergoing HD.

Low-density-lipoprotein apheresis-mediated endothelial activation therapy to severe-peripheral artery disease study: Rationale and study design.

A novel approach is required for standard therapy-resistant peripheral arterial disease (PAD). This is a single-center, single-arm, interventional study (LDL Apheresis-Mediated Endothelial Activation Therapy to Severe-Peripheral Artery Disease study), which aims to evaluate the efficacy and safety of lipoprotein apheresis (LA) with a dextran sulfate cellulose column in PAD with controlled serum cholesterol levels. The study participants have standard therapy-resistant PAD with controlled serum cholesterol levels. A total of 35 patients undergo 10 sessions of LA therapy. The ankle-brachial index and vascular quality of life questionnaire are assessed before and after the treatment period as primary outcomes. Registration of patients began in November 2015 and is planned to be concluded in October 2020.

Infiltration of CD4, CD8, CD56, and Fox-P3-positive lymphocytes in breast carcinoma tissue after neoadjuvant chemotherapy with or without trastuzumab.

BACKGROUND: Trastuzumab (Tz) is assumed to prime antibody-dependent cellular cytotoxicity (ADCC); however, it remains unclear whether Tz therapy can clinically induce adaptive cellular immunity. OBJECTIVE: Adaptive Cellular Immune Effect of Tz Therapy. METHODS: This study included 29 surgical invasive breast carcinomas administered neoadjuvant chemotherapy with Tz (15 cases) or without Tz (14 cases). The numbers of immunoreactive cells (CD4, CD8, CD56, and Fox-P3) in three different compartments (intratumoral, adjacent stromal, and distant stromal) were determined. RESULTS: The average number of adjacent stromal CD4-positive, CD8-positive, and Fox-P3-positive cells in the Tz+ group was significantly greater than that in the Tz- group (p = 0.036, 0.0049, and 0.043, respectively). However, the number of Fox-P3-positive cells was much less than that of CD4-positive cells. Moreover, distant stromal CD4-positive and CD8-positive cells in the Tz+ group was also significantly greater than that of the Tz- group (p = 0.029 and 0.032, respectively). Only a small number of CD56-positive natural killer cells, playing a main role in ADCC, accumulated at the tumor site after Tz therapy. CONCLUSIONS: The results suggest that Tz therapy induces adaptive cellular immunity, including infiltration of both CD4-positive helper T cells and CD8-positive cytotoxic T cells into the breast carcinoma lesion.

[Two Cases of Unresectable/Advanced Breast Cancer with Pathological Complete Response after Combination Chemotherapy with Pertuzumab. Trastuzumab, and Docetaxel].

Combination chemotherapy with pertuzumab, trastuzumab, and docetaxel is recommended as the first-line treatment for patients with HER2-positive unresectable or metastatic breast cancer. We report 2 cases of unresectable breast cancer for which pertuzumab, trastuzumab, and docetaxel therapy was effective. Case 1: A woman in her 40s was diagnosed with TxN3aM0, Stage ⅢC, HER2-positive, hormone receptor-positive advanced breast cancer. After administration of 6 courses of pertuzumab, trastuzumab, and docetaxel therapy, she underwent surgery(Bt+Ax[Ⅱ]). Histopathological examination revealed that chemotherapy effect was Grade 3. Case 2: A woman in her 60s was diagnosed with de novo Stage Ⅳ, HER2- positive, hormone receptor-negative breast cancer. She was administered 8 courses of pertuzumab, trastuzumab, and docetaxel therapy as the third-line treatment, because she initially refused treatment. Thereafter, she underwent surgery(Bt+Ax [Ⅰ]). In both cases, histopathological examination revealed complete response after chemotherapy. Thus, combination therapy of pertuzumab and trastuzumab may improve the prognosis in patients with HER2-positive breast cancer.

[A Case of Breast Metastasis of Eccrine Porocarcinoma].

An 80's woman was diagnosed with eccrine porocarcinoma of the head in 2010.T he tumor was removed surgically but relapsed in the cervical and axillary lymph nodes 2 years later.The patient underwent surgery, and received systemic chemotherapy and radiation.Chest CT after treatment revealed an irregular mass and thickened skin in the left breast.Core needle biopsy specimens were used to diagnose metastasis of eccrine porocarcinoma.A wide excision with a 1 cm margin was performed under local anesthesia.After surgery, supraclavicular lymph node recurrence was detected.The patient received palliative care because there was no effective treatment available.Eccrine porocarcinoma is a rare malignant tumor of the intraepidermal sweat duct.Breast metastasis from malignant disease is also rare.To our knowledge, breast metastasis of eccrine porocarcinoma has not been reported.

Immunohistochemical analyses of CD44 variant isoforms in invasive micropapillary carcinoma of the breast: comparison with a concurrent conventional invasive carcinoma of no special type component.

BACKGROUND: Invasive micropapillary carcinoma (IMPC) is a distinct histopathological variant of breast carcinoma and frequently develops lymph node metastases. CD44 is a family of transmembrane glycoprotein receptors with multiple variant isoforms (CD44v), which have tissue-specific expression. Previous studies have demonstrated a loss or gain of CD44v and CD44 standard form (CD44s) expression in breast carcinomas. In this study, we analyzed the immunoprofiles of CD44s, CD44v6, and CD44v9 in IMPC and compared them with those in a concurrent invasive carcinoma of no special type (ICNST) component, thus clarifying the significance of CD44 expression in IMPC. METHODS: Twenty-one consecutive cases of mixed IMPC were included in this study. The expression statuses of CD44s, CD44v6, and CD44v9 in both the IMPC and ICNST components were analyzed semiquantitatively by immunohistochemistry. RESULTS: The immunohistochemical scores of CD44s, CD44v6, and CD44v9 were significantly decreased in the IMPC component compared to the ICNST component (p = 0.00335 for CD44s, p = 0.000982 for CD44v6, and p = 0.00271 for CD44v9). Moreover, the immunohistochemical scores of CD44v6 in the IMPC component and CD44v9 in the ICNST component of lymph node metastasis cases were significantly lower compared to cases without lymph node metastasis (p < 0.01). CONCLUSIONS: Decreased CD44 expression may play an important role in promoting lymph node metastasis in IMPC through an inability or decreased capacity to bind with the surrounding stroma. Moreover, high CD44s+ expression levels in the concurrent ICNST component may be related to the development of IMPC.

Hemodynamic-based Mapping of Neural Activity in Medetomidine-sedated Rats using a 1.5T Compact Magnetic Resonance Imaging System: A Preliminary Study.

The use of compact magnetic resonance (MR) systems for the neuroimaging of small animals is spreading. We investigated the potential of such systems in functional MR imaging (fMRI) of somatosensory cortex activity elicited by forepaw stimulation in medetomidine-sedated rats. Using a 1.5-tesla compact imager, we detected maximum activity with an electrophysiologically optimized frequency of 9 Hz in 3 appropriately sedated rats. With this compact system, we successfully mapped neural activity by combining optimum stimulation for a large hemodynamic response with appropriate anesthesia, thus demonstrating the utility of such systems in hemodynamic-based fMRI in preclinical and translational research.