Relationship Between Medical Therapy, Long-Term Care Insurance, and Comorbidity in Elderly Patients With Heart Failure With Systolic Dysfunction.

BACKGROUND: Although guideline-directed medical therapy (GDMT), including ß-blockers, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), improves survival and quality of life, most patients with heart failure with reduced (HFrEF) and mildly reduced (HFmrEF) ejection fraction are treated with inadequate medications. We investigated the prescription patterns of GDMT in elderly patients with HFrEF and HFmrEF and their characteristics, including the certification of long-term care insurance (LTCI), which represents frailty and disability.Methods and Results: This retrospective cross-sectional study analyzed 1,296 elderly patients with symptomatic HFrEF and HFmrEF with diuretic use (median age 78 years; 63.8% male; median left ventricular ejection fraction 40%). Prescription rates of GDMT were inadequate (ACEi, ARBs, ß-blockers, and MRAs: 27.0%, 30.1%, 54.1%, and 41.9%, respectively). LTCI certification was independently associated with reduced prescription of all medications (ACEi/ARB: odds ratio [OR] 0.591, 95% confidence interval [CI] 0.449-0.778, P=0.001; ß-blockers: OR 0.698, 95% CI 0.529-0.920, P<0.001; MRAs: OR 0.743, 95% CI 0.560-0.985, P=0.052). Patients with LTCI certification also had a high prevalence of polypharmacy and prescription of diuretics. CONCLUSIONS: Vulnerable patients with LTCI may be an explanation for the challenges in implementing GDMT, and communicating is required for favorable heart failure care in this population.

Monte Carlo study of cuprate superconductors in a four-bandd-pmodel: role of orbital degrees of freedom.

Understanding the various competing phases in cuprate superconductors is a long-standing challenging problem. Recent studies have shown that orbital degrees of freedom, both Cuegorbitals and Oporbitals, are a key ingredient for a unified understanding of cuprate superconductors, including the material dependence. Here we investigate a four-bandd-pmodel derived from the first-principles calculations with the variational Monte Carlo method, which allows us to elucidate competing phases on an equal footing. The obtained results can consistently explain the doping dependence of superconductivity, antiferromagnetic and stripe phases, phase separation in the underdoped region, and also novel magnetism in the heavily-overdoped region. The presence ofporbitals is critical to the charge-stripe features, which induce two types of stripe phases withs)-wave andd-wave bond stripe. On the other hand, the presence ofdz2orbital is indispensable to material dependence of the superconducting transition temperature (Tc), and enhances local magnetic moment as a source of novel magnetism in the heavily-overdoped region as well. These findings beyond one-band description could provide a major step toward a full explanation of unconventional normal state and highTcin cuprate supercondutors.

Antiresorptive Drugs and the Risk of Femoral Shaft Fracture in Men and Women With Osteoporosis: A Cohort Study Using the National Database of Health Insurance Claims of Japan.

BACKGROUND: This cohort study aimed to estimate incidence rates of femoral shaft fracture in patients who were treated with antiresorptive drugs. METHODS: We used data from the National Database of Health Insurance Claims of Japan from April 2009 and October 2016. All patients with new use of an antiresorptive drug, prescription-free period of ≥3 months, and no prior femoral fractures were included. Femoral shaft fractures were identified using a validated definition based on International Classification of Diseases, 10th revision (ICD-10) codes. Incidence rate ratios were estimated using Poisson regression, with adjustment for sex, age, and the Charlson Comorbidity Index. RESULTS: We identified 7,958,655 patients (women: 88.4%; age ≥75 years: 51.2%). Femoral shaft fractures were identified in 22,604 patients. Incidence rates per 100,000 person-years were 74.8 for women, 30.1 for men, 30.1 for patients aged ≤64 years, 47.7 for patients aged 65-74 years, and 99.0 for patients aged ≥75 years. Adjusted incidence rate ratios in patients taking versus not taking each type of antiresorptive drug were 1.00 (95% confidence interval [CI], 0.98-1.03) for bisphosphonates, 0.46 (95% CI, 0.44-0.48) for selective estrogen receptor modulators, 0.24 (95% CI, 0.18-0.32) for estrogens, 0.75 (95% CI, 0.71-0.79) for calcitonins, and 0.93 (95% CI, 0.84-1.03) for denosumab. The adjusted incidence rate ratio for alendronate was 1.18 (95% CI, 1.14-1.22). CONCLUSION: The incidence rates of femoral shaft fracture varied across patients treated with different antiresorptive drugs. Further research on a specific antiresorptive drug can increase understanding of the risk of femoral shaft fracture.

Incidence and Risk Factors of Future Need for Long-Term Care Insurance in Japanese Elderly Patients With Left Ventricular Systolic Dysfunction.

BACKGROUND: Heart failure in elderly people causes physical and cognitive dysfunction and often requires long-term care insurance (LTCI); however, among patients with left ventricular (LV) systolic dysfunction, the incidence and risk factors of future LTCI requirements need to be elucidated.Methods and Results:The study included 1,852 patients aged ≥65 years with an echocardiographic LV ejection fraction (LVEF) ≤50%; we referred to their LTCI data and those of 113,038 community-dwelling elderly people. During a mean 1.7-year period, 332 patients newly required LTCI (incidence 10.7 per 100 person-years); the incidence was significantly higher than that for the community-dwelling people (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.32-1.64). On multivariate analysis, the risk factors at the time of echocardiography leading to future LTCI requirement were atrial fibrillation (HR, 1.588; 95% CI, 1.279-1.971), history of stroke (HR, 2.02; 95% CI, 1.583-2.576), osteoporosis (HR, 1.738; 95% CI, 1.253-2.41), dementia (HR, 2.804; 95% CI, 2.075-3.789), hypnotics (HR, 1.461; 95% CI, 1.148-1.859), and diuretics (HR, 1.417; 95% CI, 1.132-1.773); however, the LVEF was not a risk factor (HR, 0.997; 95% CI, 0.983-1.011). CONCLUSIONS: In elderly patients with LV systolic dysfunction, the incidence of LTCI requirement was more common than that for community-dwelling people; its risk factors did not include LVEF, but included many other non-cardiac comorbidities and therapies, suggesting the need for interdisciplinary cooperation to prevent disabilities.

MIHARI project, a preceding study of MID-NET, adverse event detection database of Ministry Health of Japan-Validation study of the signal detection of adverse events of drugs using export data from EMR and medical claim data.

We studied the effectiveness of the direct data collection from electronic medical records (EMR) when it is used for monitoring adverse drug events and also detection of already known adverse events. In this study, medical claim data and SS-MIX2 standardized storage data were used to identify four diseases (diabetes, dyslipidemia, hyperthyroidism, and acute renal failure) and the validity of the outcome definitions was evaluated by calculating positive predictive values (PPV). The maximum positive predictive value (PPV) for diabetes based on medical claim data was 40.7% and that based on prescription data from SS-MIX2 Standardized Storage was 44.7%. The PPV for dyslipidemia was 50% or higher under either of the conditions. The PPV for hyperthyroidism based on disease name data alone was 20-30%, but exceeded 60% when prescription data was included in the evaluation. Acute renal failure was evaluated using information from medical records in addition to the data. The PPV for acute renal failure based on the data of disease names and laboratory examination results was slightly higher at 53.7% and increased to 80-90% when patients who previously had a high serum creatinine (Cre) level were excluded. When defining a disease, it is important to include the condition specific to the disease; furthermore, it is very useful if laboratory examination results are also included. Therefore, the inclusion of laboratory examination results in the definitions, as in the present study, was considered very useful for the analysis of multi-center SS-MIX2 standardized storage data.

Effective dose estimation in cone-beam computed tomography for dental use by Monte-Carlo simulation optimizing calculation numbers using a step-and-shoot method.

OBJECTIVE: The objective of this study was to perform effective dose estimation in cone-beam CT for dental use (CBCT) using a Monte-Carlo simulation employing a step-and-shoot method as well as to determine the optimal number of steps. METHODS: We simulated 3DX Accuitomo FPD8 as a CBCT model and estimated the effective doses of a large and a small field of view (FOV) examination against the virtual Rando phantom using a particle and heavy ion transport code system. We confirmed the results compared to those from a thermo-luminescence dosemeter (TLD) system in a real phantom and investigated how the reduced angle calculations could be accepted. RESULTS: The effective doses of both FOVs estimated with each one degree were almost the same as those estimated from the TLD measurements. Considering the effective doses and the itemized organ doses, simulation with 5° and 10° is acceptable for the large and small FOV, respectively. We tried to compare an effective dose with a large FOV as well as with multiple small FOVs covering the corresponding area and found that the effective dose from six small FOVs was approximately 1.2 times higher than that of the large FOVs. CONCLUSION: We successfully performed a Monte-Carlo simulation using a step-and-shoot method and estimated the effective dose in CBCT. Our findings indicate that simulation with 5° or 10° is acceptable based on the FOV size, while a small multiple FOV scan is recommended from a radiation protection viewpoint.

Verification of a cocktail approach for quantitative drug-drug interaction assessment: a comparative analysis between the results of a single drug and a cocktail drug.

A cocktail approach is a method to comprehensively evaluate the activity of cytochrome P450 enzymes (CYPs) by co-administering multiple CYP substrates. This is the first report that compares the results from a cocktail study to a single substrate separate administration study (single study) with concomitant administration of CYP inducers/inhibitors. The validity of a cocktail study for use as a quantitative drug-drug interactions (DDIs) assessment was evaluated.We administered a cocktail drug (caffeine, losartan, omeprazole, dextromethorphan, midazolam) with rifampicin, cimetidine or fluvoxamine. A comparative analysis was performed between the results of a cocktail study and single studies. The results of single studies were obtained from a literature review and the trials of single substrate separate administration.A strong positive correlation of the AUC ratio of all drugs between single studies and the cocktail study was obtained. The ratio of AUC change of 12 combinations converged to 0.82-1.09, and 2 combinations ranged between 0.74-1.32.The differences in the degree of interaction between the single studies and cocktail study are acceptable to evaluate DDIs for almost all combinations. Our results indicate that a cocktail study is an adequate and quantitative evaluation method for DDIs.

Cost-utility Analysis of Rotavirus Vaccines Including the Latest Evidence and Data as of June 2020 in Japan.

BACKGROUND: In several health economic analyses of rotavirus vaccines in Japan, all were not cost-effective from the healthcare payer perspective (HPP) but generally cost-effective from the societal perspective (SP). However, few studies have incorporated clinically significant factors of vaccine herd immunity, convulsions with gastroenteritis, encephalopathies, nosocomial infections, death, and intussusception as a vaccine side effect. A cost-utility analysis incorporating these were conducted. METHODS: We used Bakir's decision-tree model and data in Japan with 94% coverage rate, 5-year time horizon, and 2% discount. We compared the incremental cost-effectiveness ratio (ICER) with a willingness-to-pay of Japanese Yen (JPY) 5 million from HPP and SP. Scenario 1 examined items based on existing research; scenario 2 additionally examined the above-mentioned items. In scenario 2, break-even prices were determined, and one-way and probabilistic sensitivity analyses were performed. RESULTS: In scenario 1, the ICER was JPY 6,057,281 from the HPP and dominant from the SP. In scenario 2, it was JPY 3,713,488 from the HPP. From the HPP in scenario 2, break-even prices were JPY 34,227 for an ICER of JPY 5 million and JPY 17,798 for cost-saving. One-way sensitivity analysis showed ICERs fluctuated widely with ambulatory visits and vaccination costs. In the probabilistic sensitivity analysis, ICERs of 54.8% were less than the willingness-to-pay. In scenario 2, from the SP, vaccines were dominant. CONCLUSION: From the HPP in scenario 2, the vaccines were cost-effective. In the sensitivity analyses, ICERs also improved from the HPP over previous studies. Herd immunity for ambulatory visits contributed most to the decline.

Population/regional differences in efficacy of 3 drug categories (antidiabetic, respiratory and psychotropic agents) among East Asians: A retrospective study based on multiregional clinical trials.

AIMS: This study aimed to identify population/regional differences in drug efficacy and the influencing factors among East Asians to be considered when planning multiregional clinical trials (MRCTs) to facilitate rapid drug approval in Asians. METHODS: A retrospective analysis of efficacy (intergroup difference in endpoint between control and study drug treatment) among East Asian populations for 3 drug categories, antidiabetic, respiratory and psychotropic agents, was conducted in collaboration with pharmaceutical companies using their MRCT data. Common endpoints by drug category were selected; background factors that commonly affected the endpoints among regions were analysed first; then the population/regional differences were evaluated by the interaction term region-by-treatment using an analysis of covariance model after adjusting for background factors. RESULTS: Among 17 endpoints for eight pharmaceutical products from 3 drug categories, no substantial population/regional differences were detected in the 3 drug categories examined (P > .05), except for haemoglobin A1c change between Japan and Korea for an antidiabetic drug, insulin glulisine (P = .0068). However, no such regional differences were evident in patients with clinically important higher haemoglobin A1c baseline values (majority subgroup). Variability in disease severity at baseline and concomitant drugs were determined to be potential influencing factors for regional differences. CONCLUSIONS: This study suggests that the regional variability in efficacy of these 3 drug categories is not large among East Asians, and reveals the importance of considering background factors when planning MRCTs. Further studies are needed to evaluate regional variability in the efficacy of other drug categories and clarify the factors leading to regional differences in East Asians.

Impact and attribute of each obesity-related cardiovascular risk factor in combination with abdominal obesity on total health expenditures in adult Japanese National Health insurance beneficiaries: The Ibaraki Prefectural health study.

BACKGROUND: The aim of this study was to examine the attribution of each cardiovascular risk factor in combination with abdominal obesity (AO) on Japanese health expenditures. METHODS: The health insurance claims of 43,469 National Health Insurance beneficiaries aged 40-75 years in Ibaraki, Japan, from the second cohort of the Ibaraki Prefectural Health Study were followed-up from 2009 through 2013. Multivariable health expenditure ratios (HERs) of diabetes mellitus (DM), high low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), and hypertension with and without AO were calculated with reference to no risk factors using a Tweedie regression model. RESULTS: Without AO, HERs were 1.58 for DM, 1.06 for high LDL-C, 1.27 for low HDL-C, and 1.31 for hypertension (all P < 0.05). With AO, HERs were 1.15 for AO, 1.42 for DM, 1.03 for high LDL-C, 1.11 for low HDL-C, and 1.26 for hypertension (all P < 0.05, except high LDL-C). Without AO, population attributable fractions (PAFs) were 2.8% for DM, 0.8% for high LDL-C, 0.7% for low HDL-C, and 6.5% for hypertension. With AO, PAFs were 1.0% for AO, 2.3% for DM, 0.4% for low HDL-C, and 5.0% for hypertension. CONCLUSIONS: Of the obesity-related cardiovascular risk factors, hypertension, independent of AO, appears to impose the greatest burden on Japanese health expenditures.

Assessing the Effectiveness of Risk Communication for Maintenance Workers Who Deal With Induced Radioactivity Management of Medical Linear Accelerators.

In Japan, an amended law that mandates levels of unintended induced radioactivity has been in effect since 1 April 2012. According to the new regulation, if the concentration of induced radioactivity in affected parts is above the clearance level, the parts must be regarded as radioactive even if they weigh less than 1 kg. This regulation reform raises several new issues concerning medical linear accelerators, including how to determine the decay period for induced radioactivity before maintenance can be performed and how to identify what parts should be considered radioactive waste. The authors performed several risk communication (RC) activities aimed at improving the understanding of maintenance workers at medical accelerator manufacturers and establishing good guidelines by involving stakeholders. For this purpose, a working group was established and conducted RC activities, such as holding opinion exchange meetings between medical staff and maintenance workers and creating a booklet to answer questions from maintenance workers. To evaluate these activities, three questionnaire surveys were conducted between 2011 and 2014. According to the results of this study, the ratio of maintenance workers who accepted "The decay period is within one week" was approximately 60% at the third survey and significantly increased (P < 0.0001) during the survey period. Approximately 25% of the maintenance workers felt that not enough information was provided about the decay period, and approximately 63% thought that the information provided on the health effects of radiation was sufficient. These results suggest that the present RC was successful.

High rate of awarding compensation for claims of injuries related to clinical trials by pharmaceutical companies in Japan: a questionnaire survey.

INTRODUCTION: International norms and ethical standards have suggested that compensation for research-related injury should be provided to injured research volunteers. However, statistical data of incidence of compensation claims and the rate of awarding them have been rarely reported. METHOD: Questionnaire surveys were sent to pharmaceutical companies and medical institutions, focusing on industry-initiated clinical trials aiming at new drug applications (NDAs) on patient volunteers in Japan. RESULTS: With the answers from pharmaceutical companies, the incidence of compensation was 0.8%, including 0.06% of monetary compensation. Of the cases of compensation claims, 99% were awarded. In turn, with the answers from medical institutions, the incidence of compensation was 0.6%, including 0.4% of serious but not death cases, and 0.04% of death cases. Furthermore, most claims for compensation were initiated by medical institutions, rather than by the patients. On the other hand, with the answers from clinical trial volunteers, 3% of respondents received compensations. These compensated cases were 25% of the injuries which cannot be ruled out from the scope of compensation. CONCLUSION: Our study results demonstrated that Japanese pharmaceutical companies have provided a high rate of compensation for clinical trial-related injuries despite the possibility of overestimation. In the era of global clinical development, our study indicates the importance of further surveys to find each country's compensation policy by determining how it is being implemented based on a survey of the actual status of compensation coming from statistical data.

Incremental shuttle walk test as a valuable assessment of exercise performance in patients with pulmonary arterial hypertension.

BACKGROUND: Nearly all clinical trials investigating patients with pulmonary arterial hypertension (PAH) have used the 6-min walk test (6MWT) to evaluate exercise tolerance. The incremental shuttle walk test (SWT), however, has been proposed as a more valid and reproducible alternative to the 6MWT in the evaluation of exercise tolerance in patients with chronic obstructive pulmonary disease. The efficacy of SWT in clinical practice to evaluate the exercise capacity of patients with PAH was investigated. METHODS AND RESULTS: The peak oxygen consumption (pVO2) and oxygen consumption at anaerobic threshold (VO2 at AT), the gold standard for measurement of exercise tolerance, 6MWT and SWT were measured in 19 clinically stable PAH patients (WHO functional class II-III) and the data compared. There was a higher correlation between SWT walk distance and pVO2 than between 6MWT walk distance and pVO2 (r=0.866 and 0.765, respectively; P<0.05), and a higher correlation between SWT walk distance and VO2 at AT than between 6MWT walk distance and VO2 at AT (r=0.775 and 0.587, respectively; P<0.05). No adverse events occurred during the exercise tests. CONCLUSIONS: SWT is a better reflection than 6MWT of exercise tolerance in PAH patients, and thus is a preferable alternative for assessment of exercise tolerance in PAH patients.

[Evaluation of a risk communication approach for maintenance staff working with induced radioactivity in medical linear accelerators].

In order to promote consensus building on decommissioning operation rules for medical linear accelerators in Japan, we carried out a risk communication (RC) approach mainly providing knowledge for maintenance staff regarding induced radioactivity. In February 2012, we created a booklet (26 pages) to present an overview of the amended law, the mechanism and the distribution of induced radioactivity showing the actual radiation dose rate around a linear accelerator and actual exposure doses to staff. In addition, we co-sponsored a seminar for workers in this field organized by the Japan Medical Imaging and Radiological Systems Industries Association to explain the contents of this booklet, and answer questions regarding induced radioactivity of linear accelerators as an RC program. As a result, the understanding of staff regarding the regulations on maximum X-ray energy on linear accelerators (P<0.05), and the outline of clearance systems (P<0.01), were facilitated by RC. In addition, we found that about 70% of maintenance staff considered that the cooling time for decommissioning operation depended on the situation. Our RC approach suggests that consensus building should be used to make rules on decommissioning operations for linear medical accelerators.

Relationship between cold temperature and cardiovascular mortality, with assessment of effect modification by individual characteristics: Ibaraki Prefectural Health Study.

BACKGROUND: Cold temperature has been reported to contribute to cardiovascular mortality, but it is not clear which people are more susceptible to cold temperature. METHODS AND RESULTS: The relationship between ambient temperature and mortality was examined in 3,593 subjects from the Ibaraki Prefectural Health Study who died of cardiovascular disease during a mean follow-up period of 9.7±4.0 years. Daily values of meteorological variables were obtained from the Japan Meteorological Agency. Time-stratified case cross-over analysis was used. The multivariate odds ratios (ORs; 95% confidence interval) per 1°C decrease in daily maximum temperature over the day of death and the 2 days prior to this day adjusted for relative humidity were 1.018 (1.003-1.034) for all cardiovascular deaths and 1.025 (1.003-1.048) for stroke deaths. Risk-stratified analysis showed that younger subjects aged <80 years and those with hyperglycemia were more susceptible to cold temperature. The OR of all cardiovascular deaths related to cold temperature was 1.034 (1.012-1.056) for subjects aged <80 years, and that of stroke deaths was 1.076 (1.023-1.131) for those with hyperglycemia. CONCLUSIONS: Exposure to cold temperature triggers cardiovascular deaths. Additionally, younger age and hyperglycemia could enhance susceptibility to cold temperature.

Monte Carlo study of an unconventional superconducting phase in iridium oxide J(eff)=1/2 Mott insulators induced by carrier doping.

Based on a microscopic theoretical study, we show that novel superconductivity is induced by carrier doping in layered perovskite Ir oxides where a strong spin-orbit coupling causes an effective total angular momentum J(eff)=1/2 Mott insulator. Using a variational Monte Carlo method, we find an unconventional superconducting state in the ground state phase diagram of a t(2g) three-orbital Hubbard model on the square lattice. This superconducting state is characterized by a d(x(2)-y(2))-wave "pseudospin singlet" formed by the J(eff)=1/2 Kramers doublet, which thus contains interorbital as well as both singlet and triplet components of t(2g) electrons. The superconducting state is found stable only by electron doping, but not by hole doping, for the case of carrier doped Sr2IrO4. We also study an effective single-orbital Hubbard model to discuss the similarities to high-T(c) cuprate superconductors and the multiorbital effects.

[Estimation of cost-saving for reducing radioactive waste from nuclear medicine facilities by implementing decay in storage (DIS) in Japan].

DIS has not yet been implemented in Japan as of 2011. Therefore, even if risk was negligible, medical institutions have to entrust radioactive temporal waste disposal to Japan Radio Isotopes Association (JRIA) in the current situation. To decide whether DIS should be implemented in Japan or not, cost-saving effect of DIS was estimated by comparing the cost that nuclear medical facilities pay. By implementing DIS, the total annual cost for all nuclear medical facilities in Japan is estimated to be decreased to 30 million yen or less from 710 million yen. DIS would save 680 million yen (96%) per year.

Radiologic assessment of a self-shield with boron-containing water for a compact medical cyclotron.

The cyclotron at our hospital has a self-shield of boron-containing water. The amount of induced radioactivity in the boron-containing water shield of a compact medical cyclotron has not yet been reported. In this study, we measured the photon and neutron dose rates outside the self-shield during cyclotron operation. We estimated the induced radioactivities of the boron-containing water used for the self-shield and then measured them. We estimated the activation of concrete outside the self-shield in the cyclotron laboratory. The thermal neutron flux during cyclotron operation was estimated to be 4.72 × 10(2) cm(-2) s(-1), and the activation of concrete in a cyclotron laboratory was about three orders of magnitude lower than the clearance level of RS-G-1.7 (IAEA). The activity concentration of the boron-containing water did not exceed the concentration limit for radioactive isotopes in drainage in Japan and the exemption level for Basic Safety Standards. Consequently, the boron-containing water is treatable as non-radioactive waste. Neutrons were effectively shielded by the self-shield during cyclotron operation.

Efficiency of rejection-free methods for dynamic Monte Carlo studies of off-lattice interacting particles.

We calculate the efficiency of a rejection-free dynamic Monte Carlo method for d-dimensional off-lattice homogeneous particles interacting through a repulsive power-law potential r(-p). Theoretically we find the algorithmic efficiency in the limit of low temperatures and/or high densities is asymptotically proportional to rho(p+2)/2T(-d/2) with the particle density rho and the temperature T. Dynamic Monte Carlo simulations are performed in one-, two-, and three-dimensional systems with different powers p, and the results agree with the theoretical predictions.