University Hospital Medical Information Network Clinical Trials Registry Research Articles

Effects of Heart Rate Variability Biofeedback Training on Anxiety Reduction and Brain Activity: a Randomized Active-Controlled Study Using EEG.

Heart rate variability biofeedback (HRVBF) is a promising anxiety-reducing intervention that increases vagally-mediated heart rate variability (vmHRV) through slow-paced breathing and feedback of heart rhythm. Several studies have reported the anxiety-reducing effects of HRVBF; however, some studies have reported such training as ineffective. Furthermore, the effects of training and underlying brain activity changes remain unclear. This study examined the anxiety-reducing effects of HRVBF training and related brain activity changes by randomly assigning participants, employing an active control group, and measuring anxiety-related attentional bias using the emotional Stroop task and electroencephalography (EEG). Fifty-five healthy students with anxiety were randomly assigned to the HRVBF or control groups, and 21 in the HRVBF group and 19 in the control group were included in the analysis. Both groups performed 10 training sessions of 20min each within 3 weeks. They were assessed using resting vmHRV, event-related potential (ERP), time-frequency EEG, attentional bias, and the State-Trait Anxiety Inventory-JYZ (STAI-JYZ) before and after training. The results demonstrated increased resting vmHRV in the HRVBF group compared to the control group after training. However, no differences were observed in ERP, time-frequency EEG, attentional bias, and STAI-JYZ. Participants with higher pre-training resting vmHRV achieved higher heart rhythm coherence in HRVBF training and had reduced attentional bias. This study suggests that individuals with higher resting vmHRV are more likely to be proficient in HRVBF training and benefit from its anxiety-reducing effects. The findings contribute to participant selection to benefit from HRVBF training and modification of the training protocols for non-responders.Clinical trial registrationOrganization: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), JapanRegistration number: UMIN000047096Registration date: March 6, 2022.

Verification of the accuracy of dynamic navigation for conventional and mouthpiece methods: in vivo study.

Dynamic navigation for implant placement is becoming popular under the concept of top-down treatment. The purpose of this study is to verify the accuracy of a dynamic navigation system for implant placement. Implant placement was performed on 38 patients using 50 implant fixtures. Patients in group C were treated using a conventional method, in which thermoplastic clips were fixed to the teeth, and patients in group M were treated using thermoplastic clips fixed to a mouthpiece attached to the teeth. The groups were compared to verify whether an accuracy difference existed. A treatment planning support program for dental implants was used to superimpose the postoperative computed tomography data on the preoperative implant design data to measure the entry point, apex point, and angular deviation. The accuracy of group C was 1.36 ± 0.51mm for entry point, 1.30 ± 0.59mm for apex point, and 3.20 ± 0.74° for angular deviation. The accuracy of group M was 1.06 ± 0.31mm for the entry point, 1.02 ± 0.30mm for the apex point, and 2.91 ± 0.97° for angular deviation. Significant differences were observed in the entry and apex points between the two groups. The results indicate that group M exhibited better accuracy than group C, indicating that the stability of the thermoplastic clip is important for ensuring the accuracy of the dynamic navigation system. No previous studies have verified the accuracy of this system using the mouthpiece method, and additional data is required to confirm its accuracy for dental implant placement. The mouthpiece method improves the accuracy of implant placement and provides a safer implant treatment than the conventional method. University hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), Registration Number: UMIN000051949, URL: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view_his.cgi on August 21, 2023.

Analysis of respiratory properties using the low-frequency piezoelectric sensor in patients undergoing intravenous sedation: a prospective observational study

BackgroundPatients who undergo general anesthesia may experience respiratory failure postoperatively because of respiratory depression or upper airway obstruction. AimWe investigated whether a piezoelectric sensor (AYA-P sensor) can be used to detect upper airway obstruction in patients undergoing intravenous sedation. MethodsThis prospective observational study included 26 patients who underwent dental treatment under sedation at a dental clinic. Participants were evaluated using a newly defined airway obstruction score (AOS). The AYA-P sensors were attached to the suprasternal notch and the midpoint between the umbilicus and xiphoid process. The patient's respiratory status was classified into four categories based on thoracic movements, capnography, and breathing sounds from recorded data (S1: no airflow, S2: hypoventilation, S3: normal breathing, and S4: artifact). The data obtained from the AYA-P sensors were processed using a 0.4-Hz low-pass filter, calculated using the moving standard deviation (MSD) method, and further processed using a 0.1-Hz low-pass filter (fMSD). Next, these data were differentiated (D-fMSD). We defined the positive predictive value (PPV) as fMSD or D-fMSD values higher than a threshold α in categories S1 and S2. PPV(αMAX) was defined as the maximum PPV, and the negative predictive value (NPV[αMAX]) was defined using the same αMAX. ResultsWe compared each of the apnea-hypopnea time ratio (AHT%) and AOS with PPV(αMAX) and NPV(αMAX). The AHT% and AOS were correlated with PPV(αMAX) and NPV(αMAX) in the neck and abdomen, respectively. These findings suggest that an AYA-P sensor attached to the neck and abdomen can detect a patient's respiratory status. ConclusionProcessed data obtained from AYA-P sensors can predict upper airway obstruction in patients, and the predicted data may be dependent on individual anatomical differences. Clinical trial registrationThis study was registrated in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) clinical trial: Unique ID: UMIN000047007.

RETRACTED: Analysis of respiratory properties using the low-frequency piezoelectric sensor in patients undergoing intravenous sedation: A prospective observational study

BackgroundPatients who undergo general anesthesia may experience respiratory failure postoperatively because of respiratory depression or upper airway obstruction. AimWe investigated whether a piezoelectric sensor (AYA-P sensor) can be used to detect upper airway obstruction in patients undergoing intravenous sedation. MethodsThis prospective observational study included 26 patients who underwent dental treatment under sedation at a dental clinic. Participants were evaluated using a newly defined airway obstruction score (AOS). The AYA-P sensors were attached to the suprasternal notch and the midpoint between the umbilicus and xiphoid process. The patient's respiratory status was classified into four categories based on thoracic movements, capnography, and breathing sounds from recorded data (S1: no airflow, S2: hypoventilation, S3: normal breathing, and S4: artifact). The data obtained from the AYA-P sensors were processed using a 0.4-Hz low-pass filter, calculated using the moving standard deviation (MSD) method, and further processed using a 0.1-Hz low-pass filter (fMSD). Next, these data were differentiated (D-fMSD). We defined the positive predictive value (PPV) as fMSD or D-fMSD values higher than a threshold α in categories S1 and S2. PPV(αMAX) was defined as the maximum PPV, and the negative predictive value (NPV[αMAX]) was defined using the same αMAX. ResultsWe compared each of the apnea-hypopnea time ratio (AHT%) and AOS with PPV(αMAX) and NPV(αMAX). The AHT% and AOS were correlated with PPV(αMAX) and NPV(αMAX) in the neck and abdomen, respectively. These findings suggest that an AYA-P sensor attached to the neck and abdomen can detect a patient's respiratory status. ConclusionProcessed data obtained from AYA-P sensors can predict upper airway obstruction in patients, and the predicted data may be dependent on individual anatomical differences. Clinical trial registrationThis study was registrated in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) clinical trial: Unique ID: UMIN000047007.

Preoperatively assessed offset analgesia predicts acute postoperative pain following orthognathic surgery.

High intensity and longer duration of acute postoperative pain are generally associated with a higher risk of developing chronic postoperative pain. Therefore, it is important to identify the preoperative predictors for acute postoperative pain. Preoperative evaluation of offset analgesia (OA) and the Pain Catastrophising Scale (PCS) may be potential predictors for acute postoperative pain. This study aimed to investigate the relationship between preoperative OA, PCS, and acute postoperative pain following orthognathic surgery. Thirty patients (19 females) scheduled to undergo orthognathic surgery were included in this study. OA and PCS were evaluated preoperatively, and the patients reported their postoperative pain intensity using the visual analogue scale [0-100 mm] until it reached zero (number of days with pain). OA was induced on the dominant forearm via three consecutive painful heat pulses delivered for 5 s (T1=46 °C), 5 s (T2=47 °C), and 20 s (T3=46 °C). Subsequently, the associations between OA, PCS, and the number of days with pain were analysed. The median duration of postoperative pain was 10.3days. Multiple linear regression analysis showed a significant (p=0.0019) predictive value of OA (p=0.008) for the number of days with pain. The PCS-magnification component was positively correlated with the number of dayswith pain (R=0.369, p=0.045), with no predictive values of PCS-total and PCS-subscale scores observed. Preoperative evaluation of OA may be a new individualised, predictive tool for the number of days with acute postoperative pain following orthognathic surgery; hence, a possible biomarker for the patient's vulnerability to developing chronic postoperative pain. The study was approved by the Ethics Committee of Meikai University (A1624, A2113). This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) Clinical Trial (Unique ID: UMIN000026719, UMIN000046957).

Five-Year Clinical Outcomes of Low-Add-Power Segmented Rotationally Asymmetrical Intraocular Lens.

This study assessed 5-year results of rotationally asymmetric multifocal intraocular lens (IOL) with +1.5diopters (D) near addition (Lentis Comfort LS-313 MF15, Teleon Surgical B.V., Spankeren, Netherlands). In 38 eyes of 20 patients (76.8 ± 4.6years) who were examined at both 1 and 5years after surgery, clinical data were retrospectively collected. Corrected and uncorrected distance visual acuity (5m) and uncorrected and distance-corrected intermediate visual acuity (70cm) were excellent, with no significant differences between 1 and 5years after surgery. Uncorrected and distance-corrected near visual acuity (30cm) remained lower. Contrast sensitivity was within the normal range at both 1 and 5years. The percentage of patients who reported "never or hardly use spectacles" for far, intermediate, and near vision was 95.0%, 85.0%, and 35.0%, respectively. Glare and halo were slightly increased from 1 to 5years after surgery, but the severity remained none or mild. All patients reported "very high" or "high" level of overall satisfaction. There were no notable postoperative complications. During 5years after surgery, low-add-power segmented multifocal IOL maintained excellent distance and intermediate visual acuity as well as good contrast sensitivity. Glare and halo symptoms were mild, and patients' satisfaction level was high. University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) identifier UMIN000048353.

Plasma free amino acid profiles are associated with serum high molecular weight adiponectin levels in Japanese medical check-up population without type 2 diabetes mellitus

To prevent the progression of type 2 diabetes mellitus (T2DM), early detection and intervention are important. Several studies have already shown that the serum adiponectin level could be useful for evaluating the future risk of T2DM. Recently, plasma free amino acid (PFAA) concentrations have also emerged as potential biomarkers that predict the future onset of T2DM. In this study, we aimed to further characterise PFAA profiles by elucidating the association with the serum high molecular weight (HMW) adiponectin level in this cross-sectional study. A total of 1000 Japanese subjects who underwent medical check-ups were enrolled, and their plasma concentrations of 21 amino acids and clinical parameters were measured. The subjects without T2DM were divided into quartiles (Q1-4) by serum HMW adiponectin level, and the association with between PFAA concentrations was analysed. Concentrations of glutamate, alanine, proline, tyrosine, histidine, methionine, lysine, branched-chain amino acids (BCAAs) and tryptophan varied significantly according to the adiponectin quartile. Furthermore, serum adiponectin levels showed significant inverse correlations with these amino acids. The change in the PFAA profile in the group with the lowest adiponectin concentrations (Q1) was similar to that of T2DM patients. Although both adiponectin levels and PFAA concentrations are known to be altered by the accumulation of visceral fat and insulin resistance, the levels of glutamate, BCAA, lysine and tryptophan remain significantly associated with adiponectin level after adjustment for age, body mass index and homeostasis model assessment of insulin resistance, showing the direct association between PFAA concentrations and the serum HMW adiponectin level. Registration number: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) UMIN000029920, registered on Nov 13th 2017 (prospectively registered).

Cytokine- and Vascular Endothelial Growth Factor-Related Gene-Based Genome-Wide Association Study of Low-Dose Ketamine Infusion in Patients with Treatment-Resistant Depression.

Ketamine may work as an anti-inflammatory agent, and it increases the levels of vascular endothelial growth factor (VEGF) in patients with treatment-resistant depression. However, whether genes related to pro-inflammatory and anti-inflammatory cytokines and VEGF may predict the treatment response to ketamine remains unknown.Therefore the aim of this study was to analyze whether specific genes related to inflammatory processes and VEGF were associated with treatment response to low-dose ketamine in patients with treatment-resistant depression. Based on the genome data from our clinical trial, this study was a secondary analysis of candidate genes correlated with different timepoints of depressive symptoms. In total, 65 patients with treatment-resistant depression (n = 21 for ketamine 0.5 mg/kg, 20 for ketamine 0.2 mg/kg, and 24 for normal saline) were genotyped for 684,616 single nucleotide polymorphisms. Genes associated with 80 cytokines (i.e., interleukin [IL]-1, IL-6, tumor necrosis factor-α, and adiponectin) and VEGF (i.e., VEGF and VEGF receptors) were selected for the gene-based genome-wide association study on the antidepressant effect of a ketamine infusion. Specific single nucleotide polymorphisms, including rs2540315 and rs75746675 in IL1R1 and rs79568085 in VEGFC, were related to the rapid (within 240 min) antidepressant effect of a ketamine infusion; specific single nucleotide polymorphisms, such as Affx-20131665 in PIGF and rs8179353, rs8179353, and rs8179353 in TNFRSF8, were associated with the sustained (up to 2 weeks) antidepressant effect of low-dose (combined 0.5mg/kg and 0.2mg/kg) ketamine. Our findings further revealed that genes related to both anti-inflammatory and pro-inflammatory cytokines (i.e., IL-1, IL-2, IL-6, tumor necrosis factor-α, C-reactive protein, and adiponectin) and VEGF-FLK signaling predicted the treatment response to a ketamine infusion in patients with treatment-resistant depression. The synergic modulation of inflammatory and VEGF systems may contribute to the antidepressant effect of ketamine. University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number: UMIN000016985.

Effect of Bone Resorption Inhibitors on Serum Cholesterol Level and Fracture Risk in Osteoporosis: Randomized Comparative Study Between Minodronic Acid and Raloxifene

The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP) and selective estrogen receptor modulators (SERMs), are known to reduce serum cholesterol levels. However, the relationship between the baseline cholesterol level and incident fracture rate under the treatment using the bone resorption inhibitors has not been documented. We investigated the relation between vertebral fracture incident and the baseline cholesterol levels and cholesterol-lowering effect of N-BP and SERM in osteoporosis through a prospective randomized open-label study design. Patients with osteoporosis (n = 3986) were allocated into two groups based on the drug used for treatment: minodronic acid (MIN) (n = 1624) as an N-BP and raloxifene (RLX) as an SERM (n = 1623). Serum levels of cholesterol and incidence of vertebral fracture were monitored for 2 years. The vertebral fracture rates between the two groups were compared using the pre-specified stratification factors. The patients receiving MIN with baseline low-density lipoprotein (LDL)-cholesterol level of ≥ 140 mg/dL, high-density lipoprotein cholesterol level < 40 mg/dL, age group of ≥ 75 years, and T score of BMD ≥ -3 SD had significantly lower vertebral fracture rates than those receiving RLX (incidence rate ratios (IRR) 0.45 [95% confidence interval (CI) 0.30 0.75, p = 0.001], 0.25 [95% CI 0.09 0.65, p = 0.005], 0.71 [95% CI 0.56 0.91, p = 0.006], 0.47 [95% CI 0.30 0.75, p = 0.0012], respectively). The cholesterol-lowering effect was stronger in the RLX group than in the MIN group, regardless of prior statin use. These results indicated that MIN treatment was more effective in reducing fracture risk in patients with higher LDL cholesterol levels, although its cholesterol-lowering ability was lesser than the RLX treatment.Trial registration University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR), No. UMIN000005433; date: April 13, 2011.

Intradialytic parenteral nutrition using a standard amino acid solution not for renal failure in maintenance hemodialysis patients with malnutrition: a multicenter pilot study

BackgroundStandard amino acid solutions have recently been removed from the contraindications for use in dialysis patients in Japan. However, the details of their safety and efficacy in these patients are still not known. In this study, we investigated the safety and efficacy of intradialytic parenteral nutrition (IDPN) using ENEFLUID® injection containing standard amino acids, glucose, electrolytes, fats, and water-soluble vitamins in maintenance hemodialysis patients with malnutrition.MethodsThis clinical trial was designed as a multicenter, prospective, non-randomized, open-label, single-arm, observational pilot study. The participants were patients on maintenance hemodialysis who were in the nutritional high-risk group according to the Nutritional Risk Index for Japanese Hemodialysis Patients. One bag of ENEFLUID® injection was administered during every hemodialysis session for 12 weeks. The primary endpoint was change in serum transthyretin levels between before and after the 12-week period. As safety endpoints, we evaluated changes in body fluid volume and blood biochemical tests, including blood urea nitrogen and electrolytes, as well as blood glucose variability using flash glucose monitoring (FGM).ResultsThe mean age and body mass index of the 13 participants were 79.0 ± 10.7 years and 18.0 ± 1.7 kg/m2, respectively. No significant changes were observed in nutritional parameters, including serum transthyretin, between before and after the start of the study. After IDPN initiation, there was no obvious fluid overload or significant changes in blood biochemical tests, including electrolytes, and the treatment could be safely continued for 12 weeks. In the FGM analysis, asymptomatic hypoglycemia during hemodialysis was observed at the beginning of the study, but there was a trend toward improvement after 12 weeks (area over the curve < 70 mg/dl per dialysis session: 747.5 ± 1333.9 to 21.6 ± 54.3, P = 0.09).ConclusionsIDPN using ENEFLUID® injection can be safely continued, although it does not significantly improve markers of nutritional status. It also showed the potential to ameliorate asymptomatic hypoglycemia during hemodialysis sessions. More detailed studies of the improvement in nutritional indicators are needed.Trial registration: This study was registered with the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) on May 9, 2021 (registration ID, UMIN000044051).

Impact of the Clinical Trials Act 2018 on clinical trial activity in Japan from 2018 to 2020: a retrospective database study using new and conventional Japanese registries

ObjectiveTo clarify the impact of Japan’s Clinical Trials Act (CTA), which was enacted in April 2018, on subsequent clinical trial activity through an analysis of Japanese registry data.DesignRetrospective database study.SettingWe...

An exploratory clinical trial on the efficacy and safety of glucagon-like peptide-1 receptor agonist dulaglutide in patients with type 2 diabetes on maintenance hemodialysis

BackgroundDulaglutide is a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM). However, the efficacy and safety of dulaglutide remain unclear in insulin-treated patients with T2DM on maintenance hemodialysis (HD).MethodsDulaglutide treatment was initiated, and the insulin dose was adjusted according to the needs of individual participants. Primary outcomes were changes in the mean and standard deviation (SD) of blood glucose (BG) levels and mean amplitude of glycemic excursions (MAGE) evaluated by continuous glucose monitoring (CGM) for six days, glycated albumin (GA), glycated hemoglobin (HbA1c), pre-dialysis blood glucose levels, and daily total insulin dose from the baseline over 24 weeks. Secondary outcomes were changes in treatment satisfaction and QOL levels from the baseline, measured by using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the Diabetes Therapy-Related Quality of Life questionnaire (DTR-QOL) scores.ResultsThe analysis was performed on the 12 participants who completed the study. The GA level (median − 1.8 [interquartile range − 6.6, − 0.3] %; p = 0.026) and daily total insulin dose (− 15.0 [− 24.5, − 9.4] U/day; p = 0.002) significantly decreased without increasing hypoglycemia (area over the glucose curve < 70 mg/dL: 0.0 [− 0.2, 0.0] mg·24 h/dl; p = 0.917). Four patients successfully withdrew from insulin therapy. The levels of HbA1c, SD of BG, and MAGE showed a decreasing tendency, but no significant improvement. Regarding treatment satisfaction and QOL, the total scores of DTSQ (8.0 [0.3, 12.5]; p = 0.041) and DTR-QOL (15.5 [− 1.8, 42.0]; p = 0.023) significantly improved.ConclusionDulaglutide may help improve glycemic control, treatment satisfaction, and QOL without increasing hypoglycemia in insulin-treated patients with T2DM on maintenance HD.Trial registration This study was registered with the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) on October 11, 2016 (registration ID, UMIN000024283).

Jinhua Qinggan granule, a Chinese herbal medicine against COVID‑19, induces rapid changes in the neutrophil/lymphocyte ratio and plasma levels of IL‑6 and IFN‑γ: An open‑label, single‑arm pilot study

Traditional Chinese herbal medicine has provided clinical benefits to patients infected with coronavirus 2019 (COVID‑19) in China. Jinhua Qinggan granule (JHQGG) is a Chinese multi‑herbal formula previously developed for the treatment of H1N1 influenza and has been encouraged for use in patients with clinically suspected COVID‑19 infection. However, the immunopharmacological mechanism for the efficacy of JHQGG has not yet been confirmed. To obtain insight into this issue, the present study examined the acute effects of JHQGG ingestion on hematological and immunological parameters using uninfected individuals as subjects. For this purpose, 18 healthy volunteers were enrolled, all of whom tested negative for prior and current severe acute respiratory syndrome coronavirus 2 infection. Peripheral blood samples were collected 1 h after a single oral JHQGG administration and subjected to hematological, biochemical and cytokine tests. JHQGG rapidly induced a significant decrease in the plasma level of interleukin (IL)‑6 (P=0.00309) and an increase in the plasma level of interferon (IFN)‑γ (P=0.0268). A decrease in IL‑6 and an increase in IFN‑γ levels were observed in 14 (77.8%) and 13 (72.2%) subjects, respectively. Notably, JHQGG significantly decreased the proportion of neutrophils (P=0.00561) and increased that of lymphocytes (P=0.00485); accordingly, the neutrophil/lymphocyte ratio (NLR) was significantly reduced by JHQGG (P=0.00649). These findings suggest that the clinical benefits of the use of JHQGG against COVID‑19 are, at least in part, associated with its rapid modulatory effects on IL‑6, IFN‑γ and NLR. Considering that IL‑6 and NLR are critical biomarkers for severe COVID‑19 infection, JHQGG may thus be suitable not only for suppressing disease onset in suspected and asymptomatic cases, but also for preventing disease progression in patients with mild to severe infection. The present open‑label, single‑arm study has been prospectively registered on the University Hospital Medical Information Network‑Clinical Trials Registry (UMIN‑CTR) under the trial no. UMIN000040407 on May 15, 2020.

High Ingestion Rate of Iodine from Povidone-Iodine Mouthwash

Iodine-based mouthwash and throat sprays contain povidone iodine (PVP-I) for disinfection. PVP-I mouthwash has been commonly used for decades in Japan and other countries and frequent and/or prolonged use of PVP-I mouthwash can induce transient hypothyroidism. To assess the amount of iodine ingested from an oral rinse, 22 healthy adult volunteers (mean age: 48.1, 29–70 years) were recruited for the study. The subjects were instructed to rinse for 15 s three times with 20 mL of commercially available PVP-I mouthwash diluted into 0.23% or pure water. This method is a standardized method of gargling recommended by the manufacturers. The total iodine in the PVP-I mouthwash was measured with inductively coupled plasma-mass spectrometry. Although the 7% PVP-I mouthwash contains 7 mg of effective iodine/mL, 24.3 mg/mL of iodine was detected in the solution. The median value and ratio of the total iodine ingested were 5.0 mg (range: 2.6–10.8 mg) and 20.5% (range: 10.6–44.5%), respectively. The iodine species released from the PVP-I mouthwash are effective iodine (PVP・nHI3, I3−, and I2) and I−; however, the amount and types of iodine actually absorbed into the bloodstream are unknown. PVP-I mouthwash should be used carefully since around 5 mg of iodine could theoretically enter the body with one gargle which exceeds the tolerable upper intake level of iodine for adults. This study was prospectively registered to University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) on March 29, 2021, with the study ID of UMIN000043770.

Coix Seed May Affect Human Immune Function

Coix ( Coix lacryma-jobi Linné . var . mayuen Stapf) is, unlike many herbs used in Chinese traditional medicines, often used as a single agent. Coix seed has its specific constituents coixenolide and coixol. This review summarizes the effects of coix seed on human pathology and physiology, and the roles of coixenolide and coixol on the effects. The comprehensive literature search was conducted using PubMed, Citation Information by National Institute of Informatics of Japan (CiNii), University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), and ClinicalTrials.gov databases. Some studies suggest that coix seed promotes the spontaneous regression of viral infections of the skin. Meanwhile, kanglite, a purified oil agent used for cancer therapy, has been implied to increase the ratio of CD4 + T cells in the peripheral blood of cancer patients undergoing treatment. These studies seem to indicate that coix seed may affect cellular immune function. However, there are limitations to the individual studies on which the above consideration is based, and thereby, it is not conclusive what specific immune or clinical indices coix seed affects. In addition, the effects of coixol on human immune function have not been clarified. Therefore, coix seed seems promising for health promotion and presents a challengeable and attractive theme for natural product chemists, pharmacologists, immunologists, and clinicians.

Hematopoietic stem cell transplantation for infants with high-risk KMT2A gene–rearranged acute lymphoblastic leukemia

AbstractThe role of allogeneic hematopoietic stem cell transplantation (HSCT) for infants with acute lymphoblastic leukemia (ALL) and KMT2A gene rearrangement (KMT2A-r) is controversial in terms of both its efficacy and potential for acute and late toxicities. In Japanese Pediatric Leukemia/Lymphoma Study Group trial MLL-10, by introducing intensive chemotherapy, indication of HSCT was restricted to patients with high-risk (HR) features only (KMT2A-r and either age <180 days or presence of central nervous system leukemia). Of the 56 HR patients, 49 achieved complete remission. Forty-three patients received HSCT in first remission including 38 patients receiving protocol-specified HSCT with conditioning consisting of individualized targeted doses of busulfan, etoposide, and cyclophosphamide. Three-year event-free survival (EFS) of 56.8% (95% confidence interval [CI], 42.4% to 68.8%) and overall survival of 80.2% (95% CI, 67.1% to 88.5%) were accomplished. Univariable analysis showed that Interfant-HR criteria and flow cytometric minimal residual disease (MRD; ≥0.01%), both at the end of induction and at the end of consolidation (EOC), were significantly associated with poorer EFS. In the multivariable analysis, positive MRD at EOC was solely associated with poor EFS (P < .001). Rapid pretransplant MRD clearance and tailored HSCT strategy in the MLL-10 trial resulted in a favorable outcome for infants with HR KMT2A-r ALL. However, considering the high rate of potentially life-threatening toxicities and the risk of late effects, its indication should be further restricted or even eliminated in the future by introducing more effective therapeutic modalities with minimal toxicities. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.

The effect of cholecalciferol supplementation on allograft function in incident kidney transplant recipients: A randomized controlled study

It is unknown whether cholecalciferol supplementation improves allograft outcomes in kidney transplant recipients (KTRs). We conducted a single‐center randomized, double‐blind, placebo‐controlled trial of daily 4000 IU cholecalciferol supplementation in KTRs at 1‐month posttransplant. The primary endpoint was the change in eGFR from baseline to 12‐month posttransplant. Secondary endpoints included severity of interstitial fibrosis and tubular atrophy (IFTA) at 12‐month posttransplant and changes in urinary biomarkers. Of 193 randomized patients, 180 participants completed the study. Changes in eGFR were 1.2 mL/min/1.73 m2 (95% CI; −0.7 to 3.1) in the cholecalciferol group and 1.8 mL/min/1.73 m2 (95% CI, −0.02 to 3.7) in the placebo group, with no significant between‐group difference (−0.7 mL/min/1.73 m2 [95% CI; −3.3 to 2.0], p = 0.63). Subgroup analyses showed detrimental effects of cholecalciferol in patients with eGFR <45 mL/min/1.73 m2 (Pinteraction <0.05, between‐group difference; −4.3 mL/min/1.73 m2 [95% CI; −7.3 to −1.3]). The degree of IFTA, changes in urine albumin‐to‐creatinine ratio, or adverse events including hypercalcemia and infections requiring hospitalization did not differ between groups. In conclusion, cholecalciferol supplementation did not affect eGFR change compared to placebo among incident KTRs. These findings do not support cholecalciferol supplementation for improving allograft function in incident KTRs.Clinical trial registry: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN‐CTR) as UMIN000020597 (please refer to the links below). UMIN‐CTR: https://upload.umin.ac.jp/cgi‐open‐bin/ctr_e/ctr_view.cgi?recptno=R000023776

The Multi-Domain Intervention Trial in Older Adults With Diabetes Mellitus for Prevention of Dementia in Japan: Study Protocol for a Multi-Center, Randomized, 18-Month Controlled Trial

Background: The Japan-Multi-domain Intervention Trial for Prevention of Dementia in Older Adults with Diabetes (J-MIND-Diabetes) is an 18-month, multi-centered, open-labeled, randomized controlled trial designed to identify whether multi-domain intervention targeting modifiable risk factors for dementia could prevent the progression of cognitive decline among older adults with type 2 diabetes mellitus (T2DM). This manuscript describes the study protocol for the J-MIND-Diabetes trial.Materials and Methods: Subjects of this trial will comprise a total of 300 T2DM outpatients aged 70–85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the stratified permuted-block randomization methods. The intervention group will participate in multi-domain intervention programs aimed at: (1) management of metabolic and vascular risk factors; (2) physical exercise and self-monitoring of physical activity; (3) nutritional guidance; and (4) social participation. The control group will receive usual T2DM care and general instructions on dementia prevention. The primary and secondary outcomes will be assessed at baseline, at 6- and 18-month follow-up. The primary outcome is change from baseline at 18 months in a global composite score combining several neuropsychological domains, including global cognitive function, memory, attention, executive function, processing speed and language. Secondary outcomes include: (1) cognitive changes in neuropsychological tests; (2) changes in geriatrics assessments; (3) metabolic control and diabetic complications; (4) changes in blood and urinary markers.Discussion: This trial will be the first trial to demonstrate the effectiveness of multi-domain intervention in preventing cognitive decline in older adults with T2DM at increased risk of dementia in Japan.Trial Registration: UMIN000035911; Registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) 18 February 2019. (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000040908).

Qingfei Paidu decoction, a Chinese herbal medicine against COVID‑19, elevates the blood levels of pro‑inflammatory cytokines: An open‑label, single‑arm pilot study

Qingfei Paidu decoction (QFPD) is a Chinese herbal medicine newly formulated for the treatment of COVID‑19. QFPD significantly enhances the therapeutic effects of standard pharmacotherapy in mild to critically ill patients with COVID‑19. However, limited information is available on the immunological mechanisms underlying the efficacy of QFPD. In addition, the feasibility of the prophylactic administration of QFPD to uninfected individuals remains unconfirmed. To obtain insight into these issues, an open‑label, single‑arm pilot study was conducted using 19 healthy uninfected individuals as subjects, and the effects of QFPD ingestion at a dose lower than that recommended for therapeutic use on hematological and immunological parameters were examined. QFPD was prepared according to the Chinese official clinical guideline, except that the dose of each herb was reduced to 1/30 and administered orally to the participants twice daily for 3 days. Low‑dose QFPD ingestion significantly increased the plasma levels of pro‑inflammatory cytokines, tumor necrosis factor (TNF)‑α (P=0.000107), interleukin (IL)‑1β (P=0.000982), IL‑18 (P=0.00105), IL‑2 (P=0.0483) and IL‑8 (P=0.000191), key mediators of a broad spectrum of antiviral immunity. No apparent adverse effects were observed during the trial. These findings suggest that the clinical efficacy of QFPD against COVID‑19 is, at least in part, associated with its immunological activity to mimic the blood cytokine environment produced by early antiviral immune responses, which are shown to be profoundly suppressed during the early stages of COVID‑19. The daily ingestion of low‑dose QFPD may thus be a possible option for the prevention of COVID‑19 during the epidemic. The present study was prospectively registered at the University Hospital Medical Information Network‑Clinical Trials Registry (UMIN‑CTR) under the trial no. UMIN000040341 on May 9, 2020.

Efficacy and Safety of Luseogliflozin in Patients with Type2 Diabetes Complicated by Hepatic Dysfunction: A Single-Site, Single-Arm, Open-Label, Exploratory Trial.

IntroductionImprovements in glycemic control and hepatic function are clinically important goals in the treatment of patients with type 2 diabetes mellitus (T2DM) complicated by hepatic dysfunction. The favorable effects of the sodium–glucose co-transporter inhibitor luseogliflozin on hepatic dysfunction were anticipated for humans. Nevertheless, few clinical studies have confirmed its real-world efficacy on hepatic dysfunction. This trial assessed the efficacy and safety of luseogliflozin in patients with T2DM complicated by hepatic dysfunction.MethodsThis prospective, single-site, single-arm, open-label, exploratory trial included 55 subjects with T2DM complicated by hepatic dysfunction. Subjects were administered luseogliflozin and observed for 52 weeks. The primary endpoints were the change in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), and hemoglobin A1c (HbA1c) from baseline to week 52. The secondary endpoints included body weight, body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose (FPG), homeostatic model assessment beta (HOMA-β), homeostatic model assessment of insulin resistance (HOMA-IR), ferritin, Mac-2 binding protein (M2-BP), fatty liver index (FLI), fibrosis-4 (FIB-4) index, type IV collagen 7S domain, nonalcoholic fatty liver disease (NAFLD) fibrosis score, high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6).ResultsAST, ALT, γ-GTP, and HbA1c significantly decreased from baseline to week 52. Body weight, BMI, waist circumference, and FPG also significantly decreased. HOMA-IR significantly decreased but HOMA-β was unchanged. FLI, ferritin, M2-BP, and NAFLD fibrosis scores significantly decreased whereas the FIB-4 index and type IV collagen 7S domain did not significantly change. The hs-CRP and IL-6 levels did not significantly change.ConclusionLuseogliflozin administration in patients with T2DM complicated by hepatic dysfunction was well tolerated, did not worsen the hepatic condition, and might even be beneficial to improve hepatic function, reduce liver fat, and attenuate liver injury and fibrosis.Trial RegistrationThis study was registered under the University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) (No. UMIN000025808) and the Japan Registry of Clinical Trials (jRCT) (No. jRCTs021180017).