Search for Periodic Time Variations of the Solar

We report a search for time variations of the solar ^{8}B neutrino flux using 5804 live days of Super-Kamiokande data collected between May 31, 1996, and May 30, 2018. Super-Kamiokande measured the precise time of each solar neutrino interaction over 22 calendar years to search for solar neutrino flux modulations with unprecedented precision. Periodic modulations are searched for in a dataset comprising five-day interval solar neutrino flux measurements with a maximum likelihood method. We also applied the Lomb-Scargle method to this dataset to compare it with previous reports. The only significant modulation found is due to the elliptic orbit of the Earth around the Sun. The observed modulation is consistent with astronomical data: we measured an eccentricity of (1.53±0.35)%, and a perihelion shift of (-1.5±13.5) days.

Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande.

We report a search for cosmic-ray boosted dark matter with protons using the 0.37 megaton×years data collected at Super-Kamiokande experiment during the 1996-2018 period (SKI-IV phase). We searched for an excess of proton recoils above the atmospheric neutrino background from the vicinity of the Galactic Center. No such excess is observed, and limits are calculated for two reference models of dark matter with either a constant interaction cross section or through a scalar mediator. This is the first experimental search for boosted dark matter with hadrons using directional information. The results present the most stringent limits on cosmic-ray boosted dark matter and exclude the dark matter-nucleon elastic scattering cross section between 10^{-33}cm^{2} and 10^{-27}cm^{2} for dark matter mass from 1 MeV/c^{2} to 300 MeV/c^{2}.

Erratum: Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande [Phys. Rev. Lett. 130, 031802 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.031802.

Effects of polypharmacy on the prevalence of adverse drug events resulting in outpatient visits and hospitalization.

A high proportion of hospitalizations is attributable to the prevalence of adverse drug events. This retrospective study included outpatients and inpatients to determine the prevalence of adverse drug events and if polypharmacy increases it. The prevalence, classification, and causality of adverse drug events were assessed based on medical records, laboratory values, and other data. Multivariate analysis (multiple logistic regression analysis) was performed with the presence or absence of adverse drug events at the time of the visit as the dependent variable and items for which the P-value was <0.25 in the univariate analysis as independent variables. The prevalence of adverse drug events was 13.0%, 10.9%, and 16.0% among all patients, the outpatient group, and the inpatient group, respectively. Multivariate analysis showed that polypharmacy (≥5 drugs) significantly increased the risk of adverse drug events in all patients. The prevalence of adverse drug events significantly increased with each additional drug used. We expect that minimizing the number of medications through moderation of the number of prescription drugs and elimination of polypharmacy will reduce the number of outpatient visits and hospitalizations due to adverse drug events.

Safer Vitrification of Mouse and Human Embryos Using the Novel Cryoroom Vitrification System for Assisted Reproductive Technology.

BACKGROUND: Vitrification is widely used for assisted reproductive technology (ART). Most vitrification devices require the skillful placement of embryos into the carrier and aspiration of excessive vitrification solution. OBJECTIVE: To evaluate the efficacy and safety of the Cryoroom as a vitrification device. MATERIALS AND METHODS: Mouse and human embryos were vitrified with Cryoroom or Cryotop, and the developmental potency was assessed in vitro. Mouse monozygotic twin blastocysts were vitrified with Cryoroom or Cryotop for microarray analysis. RESULTS AND DISCUSSION: In mouse and human embryos, there were no differences between the survival and developmental progress in each device. In silico, the Cryoroom device showed no changes, particularly in DNA methylation after vitrification compared with the Cryotop. These results showed that the form and function of the device may affect the gene expression levels in vitrified embryos. CONCLUSION: The Cryoroom represents a safe and potentially revolutionary vitrification device for ART.

Signal detection of oral drug-induced dementia in chronic kidney disease patients using association rule mining and Bayesian confidence propagation neural network.

Among the mechanisms responsible for cognitive dysfunction in chronic kidney disease (CKD) are albuminuria and oxidative stress. However, there may be other causes not yet identified. In fact, the full relevance of CKD patient drug use and its relationship to dementia has hardly been barely investigated. We identified drugs affecting cognitive function in CKD patients by analyzing the spontaneous reporting system in Japan using Association rule mining (ARM) and Bayesian confidence propagation neural network (BCPNN). The signal detection criterion used were as follows: case ≥ 3, lift > 1, conviction > 1 (ARM) and IC025 >0 (BCPNN). Drugs with more than 20 cases were valaciclovir (lift: 11.21, conviction: 1.28, IC025: 3.12), amantadine (lift: 19.69, conviction: 1.68, IC025: 3.05), nalfurafine (lift: 8.35, conviction: 1.19, IC025: 2.18), pregabalin (lift: 6.05, conviction: 1.12, IC025: 1.78), and acyclovir (lift: 5.89, conviction: 1.12, IC025: 1.68). This study is the first report to use a large-scale medical database to identify drugs related to oral drugs-induced dementia in CKD.

Association between dipeptidyl peptidase-4 inhibitors and autoimmune disorders: Data mining of the spontaneous reporting system in Japan.

The main objective of this study is to conduct a disproportionality analysis of adverse events in the Japan Adverse Event Report (JADER) database and evaluate the risk of the DPP-4 inhibitor induced autoimmune disorder, the secondary objective is risk assessment of sex difference and age difference. The proportional reporting ratio (PRR) of frequency-based statistics and Bayesian estimates of the information components (IC) were calculated as a measure of signal detection. Sex difference and age difference were evaluated using signal score calculated from the PRR and the Chi-square. In patients taking DPP-4 inhibitors, 94 reports of autoimmune disorders were detected with both signals; PRR: 4.09, chi-square: 158.26 and IC: 1.66, 95 % confidence interval: 1.32-2.00). For other antidiabetic drugs, no signals were detected. The signal of males was PRR: 4.53, chi-square: 110.91 and signal score: 6.22, the signal of female was PRR: 3.53, chi-square: 47.65 and signal score: 5.12. About age difference, the signal scores were 6.71 for patients over 60 years and 0.56 for patients under 60 years old. This study suggests that the DPP-4 inhibitors, unlike other antidiabetic drugs, were associated with autoimmune disorders. Signals of the DPP-4 inhibitors induced autoimmune disorders were detected in both male and female, but no sex difference was observed, but age difference was observed. Especially attention should be paid to patients over 60 years old.

Community pharmacy-level factors associated with medical and nursing home facility collaboration in Japan.

The aim of this study was to clarify the community pharmacy-level factors related to experiences of and attitudes toward collaboration with medical and nursing home care facilities. We conducted a postal questionnaire survey of all pharmacies in Gifu, Japan, assessing the experiences and attitudes of supervising pharmacists regarding the following activities related to collaboration between medical facilities and nursing home care facilities: regional care meetings/service adjustment meetings, case discussion conferences, joint workshops/continuing education conferences, community service, information sharing through medical cooperation networks, and pharmacists accompanying physicians on home care visits. The factors significantly related to inter-professional collaboration were the family pharmacist guidance fee and the number of patients offered pharmaceutical care through cooperation with other medical facilities. Items on attitudes toward collaborating with other medical facilities showed similar results. Overall, policies that support inter-professional collaboration to create a foundation, establish mechanisms to facilitate collaboration, and identify collaborative activities that can be carried out at each pharmacy should be developed.

Color change in Perlodel® tablets induced by LED lighting - photolysis of bromocriptine mesylate.

Various types of fluorescent lights are found in the dispensing rooms of medical facilities, such as hospitals and pharmacies, in Japan. However, to reduce electric power consumption, it was necessary to evaluate the substitution of fluorescent lighting with light emitting diode (LED) lighting, which has become widespread in recent years. We subjectively evaluated several types of medicines stored under various light sources and found that different color changes were induced in tablets. In this study, we focused on Perlodel ® tablets, containing 2.5 mg bromocriptine mesylate, as an example for the objective evaluation of the differences in the color change of tablets when stored under LED lighting and fluorescent lighting. High-performance liquid chromatography (HPLC) analysis of part of the tablet surface area revealed a change from white to light brown or dark brown after 28 days of irradiation, with a residual concentration of bromocriptine mesylate of 85.5 % under fluorescent lighting, 85.6 % under daylight-color LED lighting, 90.3 % under bulb-color LED lighting, and 99.2 % in the dark. In addition, the ultraviolet (UV)-visible spectral study of the absorbance of a photo-product at 400-550 nm indicated that the color change of the Perlodel® 2.5 mg tablet was caused by photochemical degradation of bromocriptine mesylate. Thus, this analysis of the photochemical changes in drugs stored under different light sources demonstrated the potency of LED lights. Through the objective evaluation of the color change, the cause of the color change was determined; this will allow us to develop a strategy that minimizes possible disadvantages to patients, such as a decrease in treatment efficacy owing to decomposition of the main component or adverse caused by decomposed matter.

Relationship Between Initial Renal Function and the Inhibitory Effect of Dipeptidyl Peptidase-4 Inhibitor Treatment on Renal Function Decline.

We retrospectively investigated the renal function index of patients with type 2 diabetes mellitus (T2DM) to examine the influence of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal function between patients up to early nephropathy and after overt nephropathy. Patients with T2DM (>18 years old) who had been prescribed hypoglycemic agents for ≥3 months at Gifu Municipal Hospital between March 2010 and April 2014 were included in the study. Renal function was evaluated as the estimated glomerular filtration rate (eGFR) decline from baseline at 12 months. Patients in the DPP-4 inhibitor-treated and untreated groups with an eGFR ≥60 (358 [58.2 %] and 257 [41.8 %], respectively) and eGFR <60 (115 [60.2 %] and 76 [39.8 %], respectively) were subjected to multiple logistic regression analysis. Among patients with an eGFR ≥60, no significant differences were observed in eGFR decline rates over time. However, among patients with an eGFR <60, significant decreases were observed in eGFR decline rates >10 % (6 months; odds ratio, 0.476; P = 0.043, 12 months; odds ratio, 0.413; P = 0.010). Similar results were obtained for an eGFR decline rate >20 % (12 months; odds ratio, 0.369; P = 0.049). DPP-4 inhibitors are renoprotective in patients with T2DM and an eGFR <60.

Factors influencing the use of over-the-counter drugs and health foods/supplements.

Over-the-counter (OTC) drugs and health foods/supplements are used as means of self-medication with the aim of preventing diseases and maintaining health. No reports have yet addressed the relationship between healthcare systems and self-medication. Here, we carried out a retrospective survey to identify healthcare system factors affecting OTC drug and health food/supplement usage. Patients hospitalized at Gifu Municipal Hospital between October 1, 2014 and March 31, 2015 were given a survey. The items surveyed were age, gender, disease, alcohol intake/smoking status, insurance classification, and medical pharmaceuticals, OTC drugs, and health foods/supplements used immediately before hospitalization. We performed multiple logistic regression analysis using OTC drugs and health foods/supplements as dependent variables with patient attributes, medical insurance, etc. as independent variables. A total of 5,965 patients were analyzed. OTC users comprised 2.6 % (156 people) of the total. The use of OTC drugs was significantly higher for females and alcohol consumers than in other categories. In contrast, the use of OTC drugs was significantly lower for participants in public expense/medical subsidy programs. Health foods/supplements were used by 4.0 % of all subjects (240 people); their use was significantly higher among females and users of medical pharmaceuticals. On the other hand, the use of health foods/supplements was significantly lower for smokers, users of the latter-stage elderly healthcare system, and users of public expense/medical subsidy programs.

Clinic-level factors associated with collaboration with community pharmacies in Japan.

The aim of this study was to clarify the clinic-level factors related to experiences of and attitudes toward collaboration with community pharmacies. We conducted a postal questionnaire survey of all clinics in Gifu, Japan, assessing the experiences and attitudes of representative clinical staff regarding the following activities in collaboration with community pharmacists: regional care meetings/service adjustment meetings, case study conferences, joint workshops/continuing education conferences, community services, information sharing through medical cooperation networks, and accompanying community pharmacists during home care. The factors significantly related to experiences of joint workshops/continuing education conferences included home care visits (odds ratio [OR] 2.39) and a 100 % out-of-hospital prescription ratio (OR 4.80). In contrast, only home care visits were significantly associated with consideration of information sharing through medical cooperation networks and accompanying community pharmacists during home care (OR 2.06 and 11.91, respectively). Finally, the factors significantly associated with considering implementing case study conferences and joint workshops/continuing education conferences included home care visits (OR 4.64 and 2.98, respectively) and a 100% out-of-hospital prescription ratio (OR 4.64 and 6.38). Overall, having more opportunities to communicate with community pharmacists and other healthcare professionals appeared to facilitate clinics' consideration of collaboration with community pharmacies, along with actual experiences.

A rapid method to screen poisoning causative agents in an acute care hospital in Japan.

WHAT IS KNOWN AND OBJECTIVE: A simple, rapid analysis is required to simultaneously analyse medicinal toxicants in emergency medical care. In this regard, the analysis of blood samples by LC-MS/MS equipped with a spin column, involving a rapid, simple pretreatment, has attracted attention. In this study, sample pretreatment using a Monospin C18 column was performed to screen 11 medicinal toxicants in blood samples by LC-MS/MS. METHODS: Serum samples supplemented with 11 medical toxicants-acetaminophen, salicylic acid, nitrazepam, diphenhydramine, bromvalerylurea, phenobarbital, amitriptyline, risperidone, fenitrothion, malathion and methomyl-were pretreated with the Monospin C18 column according to Pretreatment I and Pretreatment II, followed by LC-MS/MS analysis. RESULTS AND DISCUSSION: All toxicants were not detected by a single pretreatment method but were detected by two pretreatment methods. According to Pretreatment I, 10 medicinal toxicants-excluding salicylic acid-were detected. The recovery rates of all medicinal toxicants, except acetaminophen and methomyl, were greater than or equal to 80%. Salicylic acid was detected by Pretreatment II, with a recovery rate of 57.1%. Although the coefficient of variation was less than that reported in previous methods employing SPE, the recovery rates were better possibly because of the simultaneous adsorption of water- and lipid-soluble substances and evaporation by drying. WHAT IS NEW AND CONCLUSION: As LC-MS/MS analysis using Monospin C18 can simultaneously and rapidly screen several medicinal toxicants present in blood samples, it is expected to be highly suitable for clinical settings.

Risk factors for developing infusion reaction after rituximab administration in patients with B-cell non-Hodgkin's lymphoma.

Rituximab (RTX), a monoclonal antibody against CD20, is known to cause fewer side effects than conventional anti-cancer drugs; however, infusion reaction (IR), which is specific to monoclonal antibody therapy, is frequently triggered by RTX. Therefore, we designed this study to identify risk factors based on clinical test values for developing IR after RTX administration. Eighty-nine patients with B-cell non-Hodgkin's lymphoma who had received RTX for the first time between February 2010 and March 2013, at the Gifu Municipal Hospital were enrolled as subjects. Analysis of data was conducted for 87 patients, after excluding patients whose data were missing. Univariate analysis showed significant differences in the number of patients exhibiting a soluble interleukin-2 receptor (sLL-2R) level > 2,000 U/L and hemoglobin (Hb) < lower standard limit (LSL) between the IR and non-IR groups. Multivariate analysis showed significant differences with respect to slL-2R > 2,000 U/L [odds ratio (OR), 4.463; 95% confidence interval (Cl), 1.262-15.779; P = 0.020], Hb < LSL [OR, 3.568; 95% CI, 1.071-11.890; P = 0.038], and steroid administration [OR, 0.284; 95% Cl, 0.094-0.852; P = 0.025]. Our findings show that sIL-2R > 2,000 U/L, Hb < LSL, and a lack of steroid premedication are risk factors for developing IR following RTX treatment.

Paraneoplastic cerebellar degeneration caused by ovarian clear-cell carcinoma.

Paraneoplastic cerebellar degeneration is a paraneoplastic neurological syndrome caused by the remote effect of certain systemic cancers and is characterized by subacute cerebellar symptoms. A 62-year-old woman suffering from unidentified cerebellar symptoms was admitted to our hospital. Paraneoplastic cerebellar degeneration was suspected and ovarian cancer was detected after the systemic examination for malignancy. The symptoms of vertigo and dysarthria were improved a little after surgical operation and treatments of γ-globulin, steroid pulse and tacrolimus hydrate. The cerebellar symptoms of paraneoplastic cerebellar degeneration are often evident prior to detection of malignancy. It is important to perform systemic examination for malignancy in case of unidentified cerebellar symptoms.

Simultaneous humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes.

A growing number of human tumor antigens have been described that can be recognized by cytotoxic T lymphocytes (CTLs) in a major histocompatibility complex (MHC) class I-restricted fashion. Serological screening of cDNA expression libraries, SEREX, has recently been shown to provide another route for defining immunogenic human tumor antigens. The detection of antibody responses against known CTL-defined tumor antigens, e.g., MAGE-1 and tyrosinase, raised the question whether antibody and CTL responses against a defined tumor antigen can occur simultaneously in a single patient. In this paper, we report on a melanoma patient with a high-titer antibody response against the "cancer-testis" antigen NY-ESO-1. Concurrently, a strong MHC class I-restricted CTL reactivity against the autologous NY-ESO-1-positive tumor cell line was found. A stable CTL line (NW38-IVS-1) was established from this patient that reacted with autologous melanoma cells and with allogeneic human histocompatibility leukocyte antigen (HLA)-A2(-), NY-ESO-1-positive, but not NY-ESO-1-negative, melanoma cells. Screening of NY-ESO-1 transfectants with NW38-IVS-1 revealed NY-ESO-1 as the relevant CTL target presented by HLA-A2. Computer calculation identified 26 peptides with HLA-A2-binding motifs encoded by NY-ESO-1. Of these, three peptides were efficiently recognized by NW38-IVS-1. Thus, we show that antigen-specific humoral and cellular immune responses against human tumor antigens may occur simultaneously. In addition, our analysis provides a general strategy for identifying the CTL-recognizing peptides of tumor antigens initially defined by autologous antibody.

Hepatitis C virus NS4 protein impairs the Th1 polarization of immature dendritic cells.

Dendritic cells (DCs) in chronic hepatitis C patients display impaired function, although the details remain unclear. To investigate the hepatitis C virus (HCV) protein that has the most impact on DC function, we compared five recombinant proteins and seven HCV protein genes in modulating DC phenotype and function. Immature DCs (iDCs) were established from healthy donor peripheral blood monocytes with granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4. Lipopolysaccharide was used to establish mature DCs (mDCs). Cells were then pulsed with HCV recombinant proteins or transfected with HCV plasmids and subsequently assayed for cell surface marker expression by flow cytometry. For cytokine and proliferative T-cell response analysis, DCs were cultured with autologous CD4 T cells and tuberculin purified protein derivative (PPD). Mean fluorescent intensity of CD86 was reduced in HCV protein-pulsed iDCs. Proliferative T-cell responses and Th1 cytokine concentrations were reduced with HCV nonstructural proteins (NS), particularly with HCV NS4. HCV nonstructural proteins, particularly NS4, change the iDC phenotype and reduce antigen-specific T-cell stimulatory function with Th1 cytokine reductions.

Association between Sarcopenia and Overactive Bladder in Elderly Diabetic Patients.

OBJECTIVES: To determine the association between sarcopenia and overactive bladder (OAB) in elderly diabetic patients using the Japanese version of SARC-F called SARC-F-J. DESIGN: Cross-sectional study. SETTINGS AND PARTICIPANTS: The study included 329 elderly diabetic patients (aged ≥65 years) who regularly visited the outpatient clinic at Community hospital in Japan. MEASUREMENTS: The condition of OAB was evaluated using the OAM symptom score, which involves a self-administered questionnaire, and sarcopenia was evaluated using the self-administered SARC-F-J questionnaire comprising five items. The odds ratio for OAB due to sarcopenia was calculated using multiple logistic regression analysis, with OAB as the dependent variable and sarcopenia as the explanatory variable. RESULTS: A total of 329 patients (186 males, 143 females) were included for analysis in the present study. Of these patients, 22.9% had sarcopenia and 18.7% had OAB. After adjusting the variables, the odds ratio for OAB due to sarcopenia was 4.46 (95% confidence interval [CI], 1.14-17.36, P = 0.031) and 2.09 (95% CI, 0.52-8.26, P = 0.293) for males and females, respectively. CONCLUSION: This study found that sarcopenia was significantly associated with OAB in elderly diabetic male patients based on SARC-F-J. Moreover, the possibility of the development of OAB should be considered during the medical examinations of elderly diabetic male patients with sarcopenia.

Application of several types of substrates to ficin-catalyzed peptide synthesis.

The capability of ficin, a cystine protease, to form peptide bonds was investigated using several types of N-Boc-amino acid phenyl and naphthyl esters as acyl donor components. Enzyme-catalyzed peptide synthesis was carried out under optimized reaction conditions of pH, acyl acceptor concentration and selection of the best yield organic solvent. It used a condensation of N-Boc-Ala-OpGu and Ala-pNA as a model reaction. The products were obtained in 72-96% yield using 10 different substrates, within a few minutes of reaction time.

Multi-layered network structure of amino acid (AA) metabolism characterized by each essential AA-deficient condition.

The concentrations of free amino acids in plasma change coordinately and their profiles show distinctive features in various physiological conditions; however, their behavior can not always be explained by the conventional flow-based metabolic pathway network. In this study, we have revealed the interrelatedness of the plasma amino acids and inferred their network structure with threshold-test analysis and multilevel-digraph analysis methods using the plasma samples of rats which are fed diet deficient in single essential amino acid. In the inferred network, we could draw some interesting interrelations between plasma amino acids as follows: 1) Lysine is located at the top control level and has effects on almost all of the other plasma amino acids. 2) Threonine plays a role in a hub in the network, which has direct links to the most number of other amino acids. 3) Threonine and methionine are interrelated to each other and form a loop structure.