Eye-tracking-based cognitive assessment efficiently detects mild cognitive decline in the predementia stage.

INTRODUCTION: The early detection of cognitive decline is key to maximizing the benefits of preventive and therapeutic interventions against dementia. Generally, dementia is first assessed by interview-based neuropsychological tests, but the lengthy interview and mental stress during the assessment process make screenings inefficient. We previously developed a rapid screening test for dementia using an eye-tracking technology (eye tracking-based cognitive assessment, ETCA) and reported its utility for clinically detecting cognitive impairment in dementia cases. However, the ETCA's performance in detecting people with mild cognitive decline, which is the major target population for dementia-prevention strategies, remains insufficiently examined. Therefore, this study aimed to evaluate the ETCA's performance in individuals aged 40 years and older (n = 94, mean age; 61.0 [SD 13.1] years) without being formally diagnosed with dementia. METHODS: All participants underwent both the ETCA and neuropsychological tests, including the Mini-Mental State Examination (MMSE), Rivermead Behavioral Memory Test (RBMT), and Addenbrooke's Cognitive Examination-III (ACE-III) on the same day. We examined the correlations in scores between the ETCA and each neuropsychological test. Furthermore, we selected participants who earned normal scores in each neuropsychological test and evaluated the ETCA's performance in this subgroup. RESULTS: Participants' ETCA scores correlated significantly with their scores on neuropsychological tests, including the MMSE, RBMT, and ACE-III. Notably, the ETCA scores correlated with the RBMT or ACE-III scores in individuals who showed normal scores in each neuropsychological test. CONCLUSION: The ETCA has the potential to screen mild cognitive decline efficiently at the predementia stage in nonclinical settings.

Grad-CAM-Based Investigation into Acute-Stage Fluorescein Angiography Images to Predict Long-Term Visual Prognosis of Branch Retinal Vein Occlusion.

Background/Objectives: The purpose of this study was to analyze relevant areas in acute-stage fluorescein angiography (FA) images, predicting the long-term visual prognosis of branch retinal vein occlusion (BRVO) based on gradient-weighted class activation mapping (Grad-CAM). Methods: This retrospective observational study included 136 eyes with BRVO that were followed up for more than a year post-FA. Cropped grayscale images centered on the fovea (200 × 200 pixels) were manually pre-processed from early-phase FA at the acute phase. Pairs of the cropped FA images and the best-corrected visual acuity (BCVA) in remission at least one year post-FA were used to train a 38-layer ResNet with five-fold cross-validation. Correlations between the ResNet-predicted and true (actually measured) logMAR BCVAs in remission, and between the foveal avascular zone (FAZ) area measured by ImageJ (version 1.52r) from FA images and true logMAR BCVA in remission were evaluated. The heat maps generated by Grad-CAM were evaluated to determine which areas were consumed as computational resources for BCVA prediction. Results: The correlation coefficient between the predicted and true logMAR BCVAs in remission was 0.47, and that between the acute-stage FAZ area and true logMAR BCVA in remission was 0.42 (p < 0.0001 for both). The Grad-CAM-generated heat maps showed that retinal vessels adjacent to the FAZ and the FAZ per se had high selectivity (95.7% and 62.2%, respectively). Conclusions: The Grad-CAM-based analysis demonstrated FAZ-neighboring vessels as the most relevant predictor for the long-term visual prognosis of BRVO.

Expression profile and function of secretogranin V, and its effects on the malignant behavior of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is recognized as one of the most aggressive cancers with a poor prognosis. Global expression profiling was conducted on primary ESCC tissues with distant metastases. We investigated the identification of secretogranin V (SCG5) as a promising biomarker for the detection and assessment of ESCC. SCG5 transcription levels were evaluated in 21 ESCC cell lines. Small interfering RNA-mediated knockdown experiments validated SCG5's roles in cell invasion, proliferation, and migration. We utilized a mouse subcutaneous xenograft model to assess tumor growth. SCG5 expression was measured in 164 ESCC tissues by quantitative reverse transcription quantitative polymerase chain reaction, and its association with clinicopathological parameters was investigated. SCG5 protein levels were assessed in surgically resected tissues from 177 patients with ESCC using a tissue microarray. The mRNA expression levels of SCG5 varied widely in ESCC cell lines. The in vitro cell invasion, proliferation, and migration of ESCC cells were suppressed by the knockdown of SCG5. Mouse xenograft models revealed that tumor growth was reduced by small interfering RNA-mediated SCG5 knockdown. Analysis of clinical samples demonstrated that SCG5 mRNA was expressed in ESCC compared to adjacent normal esophageal tissues. High SCG5 mRNA expression was linked to significant decreases in overall and disease-specific survival. Furthermore, SCG5 protein expression was linked to a decrease in disease-specific survival and disease-free survival. The expression of the SCG5 was significantly associated with disease-specific survival, suggesting that SCG5 may play a significant role as a diagnostic and prognostic biomarker for ESCC.

Missense BICD2 variants in fetuses with congenital arthrogryposis and pterygia.

Type 2 spinal muscular atrophy with lower extremity dominance (SMALED2) is caused by bicaudal D cargo adaptor 2 (BICD2) variants. However, the SMALED2 genotype and phenotype correlation have not been thoroughly characterized. We identified de novo heterozygous BICD2 missense variants in two fetuses with severe, prenatally diagnosed multiple arthrogryposis congenita. This report provides further insights into the genetics of this rare disease.

Fungicide Metabolite MS2 Spectral Libraries for Comprehensive Human Biomonitoring.

Fungicides undergo rapid metabolism and are excreted in the urine. There are few methods for screening these ubiquitous compounds, which have a high potential for human exposure. High-resolution mass spectrometry (HRMS) is a suitable technique to assess fungicide exposures; however, there is a lack of spectral libraries for fungicide annotation and in particular for downstream metabolites. We created spectral libraries for 32 fungicides for suspect screening. Fungicide standards were administered to mice, and 24-h urine was analyzed using hydrophilic interaction and reversed-phase chromatography coupled to hybrid quadrupole-orbitrap mass spectrometry. Suspect metabolite MS2 spectra for library creation were selected based on the ratio of exposed-to-control mouse urine. MS2 libraries were applied to urine collected from female university students (n = 73). Several tetraconazole and tebuconazole metabolites were detected in 3% (2/73) of the samples. The creation of comprehensive suspect screening MS2 libraries is a useful tool to detect fungicide exposure for human biomonitoring.

Oral hygiene status and vascular aging in schoolchildren and their mothers.

BACKGROUND: Poor oral hygiene, generally manifesting as dental caries, gingivitis, or periodontitis, is a common chronic condition among both children and adults worldwide and has been reportedly associated with hypertension and arterial stiffness mainly in adult patients. However, these associations have not been well-studied in children and adults in the general population. Therefore, we conducted this cross-sectional study to clarify the associations between oral hygiene indices and high blood pressure (BP)/hypertension and arterial stiffness as assessed by the cardio-ankle vascular index (CAVI) in children along with their mothers. The association between maternal oral hygiene and high BP in children was also examined based on the hypothesis that maternal awareness of oral hygiene is related to their children's oral hygiene. METHODS: This study was conducted as an Adjunct Study of the Aichi Regional Sub-Cohort of the Japan Environment and Children's Study. Participating children (n = 220, 85-104 months old) and their mothers (n = 217, 29-52 years old) underwent dental/intra-oral examination and BP and CAVI assessment. High BP in children and hypertension in mothers were diagnosed according to corresponding American guidelines. Logistic regression analysis or analysis of covariance was used to examine the associations of poor oral hygiene indices with BP and CAVI. RESULTS: Maternal dental caries ≥1 was associated with their hypertension (adjusted odds ratio [aOR]: 2.72, 95% confidence interval (CI): 1.12-6.61). Maternal dental plaque ≥1/3 was associated with maternal hypertension and children's high BP (aOR, 95% CI: 4.71, 1.33-16.73 and 5.67, 1.22-25.04, respectively). Maximum pocket depth ≥4 mm was associated with children's high BP (aOR: 6.85, 95% CI: 1.24-38.01). No associations were observed between oral hygiene indices and CAVI in children; however, there was a significant association between dental plaque and CAVI in mothers (F = 5.62, p < 0.01). CONCLUSIONS: The small sample size, especially the case number, made it necessary to refrain from drawing unambiguous conclusion. The hypothesis that warrants further investigation based on the present study results is that poor oral hygiene is associated with high BP in children and hypertension and arterial stiffness in mothers, and maternal oral hygiene is associated with high BP in children.

A phase-I study of second-line S-IROX for unresectable pancreatic cancer after gemcitabine plus nab-paclitaxel failure.

Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are widely used as first-line regimens for unresectable pancreatic cancer (PC). When GnP therapy is selected, considering patient age or condition, second-line FOLFIRINOX is sometimes difficult to administer owing to its toxicity. This study aimed to determine the recommended dose (RD) of S-IROX (S-1, oxaliplatin, and irinotecan combination) regimens in patients with unresectable PC after first-line GnP failure. This phase-I study used the "3 + 3" dose-escalation design with two dose levels. Patients who failed first-line GnP therapy for unresectable PC were enrolled. Oxaliplatin and irinotecan were administered on day 1, and S-1 was administered orally twice daily on days 1-7, followed by 7 days of rest. The primary endpoints were dose-limiting toxicities (DLTs) and determination of RD. The secondary endpoint was the evaluation of potential antitumor activity. Nine patients received the second-line S-IROX regimen. In level-0 (S-1, 80 mg/m2; oxaliplatin, 85 mg/m2; and irinotecan, 120 mg/m2), no patient experienced DLT; however, one patient experienced grade 3 neutropenia. At level-1 (irinotecan increased to 150 mg/m2), one of six patients experienced DLTs, including G3 diarrhea. The RD was confirmed at the level-1 dose. The response rate, disease control rate, median progression-free survival, and median overall survival were 33.3%, 77.8%, 172 (range:77-422) days, and 414 (101-685) days, respectively. One patient underwent surgery after the second-line S-IROX therapy. Second-line S-IROX treatment was deemed acceptable. The RD was set at level-1 dose (S-1, 80 mg/m2; oxaliplatin, 85 mg/m2; and irinotecan, 150 mg/m2).

Risedronate-Induced Chronic Drug Fever in a Case of Parkinson's Disease.

We present an atypical case of risedronate-induced chronic fever in an 85-year-old woman with Parkinson's disease, with a dosage regimen of 17.5 mg/week. Our patient had been administered an analgesic/antipyretic drug, acetaminophen, at a rate of 600 mg/day for treatment of a vertebral fracture that occurred relatively frequently, which might have masked the fever caused by risedronate. We noted two clinically significant indications. Firstly, blood test results do not necessarily show the cause of risedronate-induced fever, as white blood cell counts and C-reactive protein levels vary. A simple way to diagnose risedronate-induced fever is to suspend risedronate for a certain period and observe if the patient's fever lowers. Secondly, in general, cases receiving polypharmacy tend to include an analgesic antipyretic agent, which may mask the drug-induced fever. Even in patients with Parkinson's disease whose body temperature is generally unstable due to autonomic nerve system disorder, if they are administered risedronate and experience chronic fever of unknown cause, the possibility of drug fever may be considered. This study concludes that risedronate-induced chronic fever, as observed in our case, represents a rare phenomenon, and it may be necessary to reconsider treatment methods for osteoporosis.

Stratified choroidal vascular structure in treatment-naïve diabetic retinopathy.

OBJECTIVE: To analyze the anatomical choroidal vascular layers in topical treatment-naïve diabetic retinopathy (DR) eyes. DESIGN: A retrospective, clinical case-control study. METHODS: A total of 328 eyes from 228 patients with treatment-naive DR and 192 eyes matched for axial length from 174 healthy controls were enrolled in the study. Choroidal structure was quantitatively analyzed using enhanced depth imaging optical coherence tomography (EDI-OCT). Each choroidal vascular layer was divided into the choriocapillaris, Sattler's layer, and Haller's layer, and then the choroidal area (CA), luminal area (LA), stromal area (SA), and central choroidal thickness (CCT) were calculated using binarization techniques. The ratio of LA to CA was defined as the L/C ratio. RESULTS: In the choriocapillaris, CA was significantly lower in the mild/moderate non-proliferative DR (mNPDR) group than in the control group, and SA was significantly higher in all DR groups (each P < 0.01). The L/C ratio was significantly lower in all DR groups than controls (P < 0.01). In Sattler's layer, CA, LA, and SA were significantly higher in the severe NPDR (sNPDR) and PDR groups than in the control group (P < 0.01). In Haller's layer, the L/C ratio was significantly high among the PDR groups (P < 0.05). CONCLUSIONS: The choroidal parameters of DR patients by the binarization method were associated with the stage of DR, in which the choriocapillaris lumen decreased in all the DR stages. The expansion of CA seen in more advanced DR eyes mainly resulted from changes in the Sattler's and Haller's layers.

Effectiveness and safety of the simulation-based first-dose design of voriconazole.

BACKGROUND: We investigated whether the initial voriconazole (VRCZ) dosing design, as determined using simulation software with a population pharmacokinetic model of Japanese patients, impacts the effectiveness and safety when compared with VRCZ initiation according to the package insert. METHODS: In this single-center retrospective observational study, we employed records from Tosei General Hospital (a 633-bed hospital), dated April 2017 to September 2023. Eligible patients were divided into the software-based simulation group, comprising patients administered initial VRCZ dosage adjustment by pharmacists using software-based simulation, and the standard therapy group, whose dosage was administered by a physician following the package insert recommendations without simulation. The primary objective of this study was to determine the efficacy of VRCZ first-dose design in reducing the incidence of hepatotoxicity and visual symptoms. RESULTS: The median ages of enrolled participants (n = 93) were 75 (68-79) and 72 (65-78) years in the software-based simulation and standard therapy groups, respectively. Regardless of formulation, initial trough concentrations were lower in the VRCZ software-based first dosage adjustment group and higher rate within the appropriate range (1-4 µg/mL). The incidence of all-grade hepatotoxicity or visual symptoms was significantly lower in the software-based simulation group. The log-rank test revealed a significant impact on the occurrence of ≥grade 2 hepatotoxicity in the software-based first dosage adjustment group compared to that in the standard therapy group. CONCLUSIONS: The initial VRCZ dosing design using simulation software improved the achievement of appropriate initial trough concentrations and resulted in fewer occurrences of hepatotoxicity (≥grade 2) when compared with the standard therapy.

Mechanism of Stent Failure in Patients With Eruptive Calcified Nodule Treated With Rotational Atherectomy.

BACKGROUND: Percutaneous coronary intervention (PCI) for lesions with eruptive calcified nodules (CNs) is associated with worse outcomes compared with that for other calcified lesions. We aimed to clarify the relationship between eruptive CNs at index PCI, optical coherence tomography (OCT) findings at the 8-month follow-up, and clinical outcomes using serial OCT. METHODS: This retrospective observational study used data from a prospective, single-centre registry. We conducted consecutive PCI for calcified lesions requiring rotational atherectomy (RA) with OCT guidance. We categorized 51 patients (54 lesions) into those with (16 patients [16 lesions]) and without eruptive CNs (35 patients [38 lesions]). RESULTS: Post-PCI, stent expansion was comparable between the 2 groups, and CN-like protrusion was found in 75% of lesions with eruptive CNs. Follow-up OCT at 8 months revealed in-stent CNs in 54% of treated eruptive CN lesions, whereas lesions without eruptive CNs lacked in-stent CNs. Multivariate linear regression analysis demonstrated that eruptive CN was associated with maximum neointimal tissue (NIT) thickness (regression coefficient 0.303; 95% confidence interval, 0.057-0.549; P = 0.02). Consequently, patients with eruptive CNs exhibited a higher clinically driven target lesion revascularization (TLR) rate than did those without at 1 year (31.3% vs 2.9%, P = 0.009) and 5 years (43.8% vs 11.4%, P = 0.02). TLR primarily occurred in lesions with maximum eruptive CN arc angles > 180°. CONCLUSIONS: Following RA treatment with acceptable stent expansion, eruptive CNs before PCI correlated with greater NIT formation with in-stent CNs, resulting in a higher TLR rate, particularly in lesions with maximum eruptive CN arc angles exceeding 180°.

Combination of crystal growth with optical floating zone and evaluation of Nd3+:LaAlO3 crystals with the dynamic nuclear polarization of 139La and 27Al.

Producing a polarized lanthanum (La) target with high polarization and long relaxation time is crucial for realizing time-reversal violation experiments using polarized neutron beams. We use a LaAlO3 crystal doped with a small amount of Nd3+ ions for the polarized lanthanum target. Optimizing the amount of Nd3+ ions is considerably important because the achievable polarization and relaxation time strongly depend on this amount. We established a fundamental method to grow single crystals of Nd3+:LaAlO3 using an optical floating zone method that employs halogen lamps and evaluated the crystals with the dynamic nuclear polarization (DNP) method for polarizing nuclear spins. Two crystal samples were grown by ourselves and evaluated with the DNP at 1.3 K and 2.3 T for the first time, except for the target materials of protons. The enhancement of nuclear magnetic resonance signals for 139La and 27Al was successfully observed, and the enhancement factors were eventually 3.5 ± 0.3 and 13 ± 3 for the samples with Nd3+ ions of 0.05 and 0.01 mol. %, respectively. These enhancement factors correspond to absolute vector polarizations of 0.27% ± 0.02% (Nd3+ 0.05 mol. %) and 1.4% ± 0.3% (Nd3+ 0.01 mol. %). Although the obtained polarizations are still low, they are acceptable as a first step. The combination scheme of the crystal growth and the evaluation of the crystals is found to be effectively applicable for optimizing the amount of Nd3+ ions for improving the performance of the polarized target.

Clinical course and genetic analysis of a case of the amniocentesis showing chromosome 6 trisomy mosaicism.

OBJECTIVE: Herein, we present a case of mosaic trisomy 6 detected by amniocentesis. CASE REPORT: Amniocentesis (G-banding) was performed at 17 weeks of gestation; the results were 47,XY,+6[3]/46,XY[12]. Fetal screening ultrasonography showed no morphological abnormalities, and the parents desired to continue the pregnancy. The infant was delivered vaginally at 39 weeks' gestation. The male infant weighed 3002 g at birth with no morphological abnormalities. G-banding karyotype analysis performed on the infant's peripheral blood revealed 46,XY[20]. FISH analysis revealed trisomy signals on chromosome 6 in 1-4 out of 100 cells from the placenta. The single nucleotide polymorphism microarray of the umbilical cord blood revealed no abnormalities. Methylation analysis of umbilical cord blood revealed no abnormalities in PLAGL1. No disorders were observed at one year of age. CONCLUSION: When amniocentesis reveals chromosomal mosaicism, it is essential to provide a thorough fetal ultrasound examination and careful genetic counseling to support the couples' decision-making.

Rituximab and pericardiectomy with waffle procedure in constrictive pericarditis due to IgG4-related disease: A case report.

We should consider IgG4-related disease (IGRD) as one of the potential causes of constrictive pericarditis. In patients with constrictive pericarditis due to IGRD, the combination of surgical treatment and immunosuppressive therapy may be an effective strategy.

Synaptic proteomics decode novel molecular landscape in the brain.

Synapses play a pivotal role in forming neural circuits, with critical implications for brain functions such as learning, memory, and emotions. Several advances in synaptic research have demonstrated the diversity of synaptic structure and function, which can form thousands of connections depending on the neuronal cell types. Moreover, synapses not only interconnect neurons but also establish connections with glial cells such as astrocytes, which play a key role in the architecture and function of neuronal circuits in the brain. Emerging evidence suggests that dysfunction of synaptic proteins contributes to a variety of neurological and psychiatric disorders. Therefore, it is crucial to determine the molecular networks within synapses in various neuronal cell types to gain a deeper understanding of how the nervous system regulates brain function. Recent advances in synaptic proteome approaches, such as fluorescence-activated synaptosome sorting (FASS) and proximity labeling, have allowed for a detailed and spatial analysis of many cell-type-specific synaptic molecules in vivo. In this brief review, we highlight these novel spatial proteomic approaches and discuss the regulation of synaptic formation and function in the brain. This knowledge of molecular networks provides new insight into the understanding of many neurological and psychiatric disorders.

Relationship between texture perception and oral function: A preliminary study in young, healthy adults.

BACKGROUND: Oral frailty, characterised by reduced oral function, is associated with systemic health issues in older adults. Although the criteria for diminished oral function often focus on motor and secretory abilities, texture perception also plays a crucial role in health due to its impact on food intake and palatability. OBJECTIVE: This study aimed to explore the relationship between thickness discrimination ability (TDA) and oral motor and secretory functions in healthy young individuals. METHODS: Twenty-eight adults were assessed for texture perception using eight concentrations of aqueous xanthan gum solutions to determine TDA scores. Measurements of occlusal force, masticatory performance, tongue pressure, stimulated salivary flow rate and tongue-lip motor function were conducted. Spearman's correlation analysis was used to evaluate the relationship between TDA scores and oral functions. Participants were divided into high-sensitivity and low-sensitivity groups based on their TDA scores to compare oral function test results. RESULTS: The TDA scores varied among the participants, with higher scores correlating with higher masticatory performance (r = 0.41, p < .05). Masticatory performance in the high-sensitivity group was significantly higher than in the low-sensitivity group (211.9 ± 59.2 mg/dL vs. 157.9 ± 43.0 mg/dL, p = .013), with no significant differences in other oral functions. CONCLUSION: Masticatory performance was correlated with TDA, suggesting a link between the selection function of mastication and thickness discrimination. These findings highlight the potential relevance of texture perception in oral function and indicate the need for further exploration, particularly in older adults with declining oral health.

Rhodium-catalysed additive-free alkoxycarbonylation of indoles: 2,4,6-trimethylbenzoic acid-based carbonate anhydrides as a versatile alkoxycarboxyl source.

We report a CO-free approach to indole-2-carboxylic esters: rhodium-catalysed C(2)-alkoxycarbonylation of indoles with 2,4,6-trimethylbenzoic acid-based carbonate anhydrides. Selective C-O bond cleavage of the anhydrides facilitates the introduction of various alkoxycarbonyl groups. Control experiments suggest that merging a rhodium catalyst and KI promotes the in situ formation of the RhI species.

Morphogenesis of a chiral liquid crystalline droplet with topological reconnection and Lehmann rotation.

Morphogenesis is a hierarchical phenomenon that produces various macroscopic structures in living organisms, with high reproducibility. This study demonstrates that such structural formation can also be observed in a chiral liquid crystalline droplet under a temperature gradient. Through specific control of the temperature change process, we were able to switch the final structure obtained as a result of the formation via the appearance and reconnection of loop defects in the transient state during structure formation. Simultaneously, the existence of the gradient resulted in a characteristic rotational phenomenon called Lehmann rotation, which was prominently induced in the transient state. By demonstrating three-dimensional measurements of the flow field, we revealed the existence of Marangoni convection in the state. Consequently, it is indicated that the convection results in high-speed Lehmann rotation and large structural deformation with topological changes, thereby playing a significant role in the structure formation.

Effects of continuous supplementation of Acanthopanax senticosus Harms on the cardiac autonomic function of community-dwelling elderly individuals during resting and standing tests: a randomized controlled trial.

Background: Cardiac autonomic function (CAF) decreases with aging, and Acanthopanax senticosus Harms (ASH) consumption reportedly induces anti-stress effects. This study aimed to assess the effect of continuous supplementation of ASH on CAF during resting and standing tests in the elderly population. Methods: This double-blind, randomized controlled trial was conducted in the morning in a laboratory setting and was carried out between June 2017 and July 2017 at Kambaikan, Doshisha University (Karasuma-higashi-iru, Imadegawa-dori, Kamigyo-ku, Kyoto 602-8580, Japan). In total, 28 community-dwelling elderly individuals (mean ± standard deviation = 72.5 ± 4.5 years) were included. Each subject was instructed to consume ASH or placebo supplements twice daily for 4 weeks. An autonomic reflex orthostatic tolerance recorder was used to measure CAF in pre- and post-intervention phases. Parameters were measured in a seated position and included coefficient of variation of R-R intervals (CVRR), low frequency (LF), high frequency (HF), LF/HF ratio, blood pressure, and heart rate (HR). Changes in each parameter were evaluated before and after standing. All parameters were defined as the difference between the mean value obtained in a standing position for 2 min and that obtained in a 2-min seated position. Results: A two-way analysis of variance revealed a significant group-time interaction effect on CVRR, HF, and ΔLF/HF ratio. Following the intervention, CVRR, HF, LF/HF ratio, systolic blood pressure (SBP), HR, ΔLF/HF ratio, ΔSBP, and ΔHR improved significantly in the ASH group only. Conclusions: Four-week supplementation of ASH improved CAF in community-dwelling elderly individuals during resting and standing tests. Clinical Trial Registration: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000031218, UMIN Clinical Trials Registry (UMIN000027251).