Real-world prescription of anti-COVID-19 drugs in hospitalized patients with COVID-19 in Japan.

OBJECTIVE: Prescription trends and patterns of anti-COVID-19 drugs in hospitalized patients were examined based on real world data to understand the use of anti-COVID-19 drugs in clinical practice in Japan. DESIGN: The longitudinal and cross-sectional study was conducted utilizing data from January 1, 2019 to December 31, 2021 of the MID-NET® medical information database, which stored the electronic medical records, administrative claim data, and diagnosis procedure combination data of patients in Japan. PARTICIPANTS: Hospitalized patients with a COVID-19-related diagnosis who received at least one anti-COVID-19 drug between April 1, 2020 and December 31, 2021. EXPOSURES: The following 14 drugs were included in this study: remdesivir, baricitinib, combination product of casirivimab and imdevimab, favipiravir, dexamethasone, ivermectin, azithromycin, nafamostat mesylate, camostat mesylate, ciclesonide, tocilizumab, sarilumab, combination product of lopinavir and ritonavir, and hydroxychloroquine. RESULTS: We identified 5,717 patients hospitalized with COVID-19 and prescribed at least one anti-COVID-19 drug. The entire cohort generally included patients over 41-50 years and more males. The most common prescription pattern was dexamethasone monotherapy (22.9%), followed by the concomitant use of remdesivir and dexamethasone (15.0%), azithromycin monotherapy (15.0%), remdesivir monotherapy (10.2%), and nafamostat mesylate monotherapy (8.5%). However, an often prescribed anti-COVID-19 drug differed depending on the period. CONCLUSIONS AND RELEVANCE: This study revealed the real-world situation of anti-COVID-19 drug prescriptions in hospitalized COVID-19 patients in Japan. A prescribed drug would depend on the latest scientific evidence, such as efficacy, safety, and approval status, at the time of prescription. Understanding the prescription of anti-COVID-19 drugs will be important for providing the most up-to-date treatments to patients and evaluating the benefit and/or risk of anti-COVID-19 drugs based on the utilization of an electronic medical record database.

Induction of antitoxic antibody and preventive effect against porcine edema disease by the pentameric Stx2eB subunit vaccine.

Porcine edema disease (ED) is an enterotoxaemia that frequently occurs in 4-12 week-old piglets and results in high mortality. ED is caused by Shiga toxin 2e (Stx2e), produced by host-adapted Shiga toxin-producing Escherichia coli (STEC) strains. We constructed a recombinant protein in which the B subunit of Stx2e (Stx2eB) was linked to Cartilage Oligomeric Matrix Protein (COMP)'s pentameric domain to enhance antigenicity to induce neutralizing antibodies against Stx2e. We evaluated the efficacy of this antigen as a vaccine on the farm where ED had occurred. The suckling piglets were divided into two groups. The pigs in the vaccinated group were intramuscularly immunized with the vaccine containing 30 µg/head of Stx2eB-COMP at 1 and 4 weeks of age. The control pigs were injected with saline instead of the vaccine. The neutralizing antibody titer to Stx2e, mortality, clinical score, and body weight was evaluated up to 11 weeks after the first vaccination. In the vaccinated group, the Stx2e neutralizing antibody was detected 3 weeks after the first vaccination, its titer increased during the following weeks. The antibody was not detected in the control group during the test period. The STEC gene was detected in both groups during the test period, but a typical ED was observed only in control pigs; the mortality and clinical score were significantly lower in the vaccinated group than in the control group. These data indicate that the pentameric B subunit vaccine is effective for preventing ED and offers a promising tool for pig health control.

Prescription trend and lactic acidosis in patients prescribed metformin before and after the revision of package insert for allowing metformin administration to patients with moderately decreased kidney function based on real-world data from MID-NET® in Japan.

Introduction: This study was conducted to understand the impact of package insert (PI) revision in Japan on 18 June 2019 to allow metformin use for patients with moderately decreased kidney function (30 ≤ estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2). Methods: A new user cohort design was employed to examine the prescription trend and the occurrence of lactic acidosis in patients prescribed metformin before and after PI revision using the Medical Information Database Network (MID-NET®). Results: From 12 May 2016 to 31 March 2020, 5,874 patients (before, n = 4,702; after, n = 1,172) were identified as new metformin users, including 1,145 patients (before, n = 914; after, n = 231) with moderately decreased kidney function. Although no marked changes in metformin prescription were observed before and after PI revision, the daily metformin dose at the first prescription decreased after PI revision. For both before and after PI revision, less than 10 cases of lactic acidosis occurred in all patients prescribed metformin, and no lactic acidosis was observed in patients with moderately decreased kidney function. Conclusion: The results of this study are useful for understanding the safety of metformin use in patients with decreased kidney function and suggest no worse impacts of PI revision in Japan, indicating no further safety concerns on metformin use in patients with moderately decreased kidney function under the situation with careful use and safety monitoring of metformin.

Prevalence of hypertensive diseases and treated hypertensive patients in Japan: A nationwide administrative claims database study.

We investigated the prevalence of hypertensive patients and treated hypertensive patients using a Japanese nationwide administrative claims database. We analyzed national database data from 2014, including all claims data, provided by the Ministry of Health, Labour and Welfare of Japan. Hypertensive diseases were identified using Japanese standardized disease codes. Among hypertensive patients, treated hypertensive patients were defined by the prescription of any antihypertensive medication, identified using national health insurance price listing codes. We calculated and compared the number and age-adjusted prevalence of hypertensive patients and treated hypertensive patients by prefecture and the proportion of these patients by the size of medical facilities. In 2014, approximately 27 million Japanese people were identified as hypertensive, among which 89.6% were treated. The age-adjusted prevalence of hypertensive patients (per 100,000 persons) among women and men was 21,414 and 21,084, respectively. The age-adjusted prevalence of treated hypertensive patients (per 100,000 persons) among women and men was 19,118 and 18,974, respectively. While the prevalence of hypertensive and treated hypertensive patients varied geographically, the prevalence remained similar between the sexes. Approximately 59% of hypertensive patients visited clinics (0 to 19 beds) in Japan. In Japan, 27 million people were diagnosed with hypertensive diseases, and approximately 90% of these patients were treated with any antihypertensive medication in 2014. The distribution of hypertensive patients varied geographically throughout Japan.

Association between adherence to warfarin and thrombotic events in patients with antiphospholipid syndrome in Japan: A claims-based retrospective cohort study.

PURPOSE: We aimed to evaluate adherence and persistence to warfarin therapy among patients with antiphospholipid syndrome (APS) and investigate the association between adherence and thrombotic events in those patients. METHODS: We conducted a retrospective cohort study using the Japan Medical Data Center claims database from 2005 to 2018. Patients with APS receiving warfarin treatment were included in this study. Adherence and persistence were evaluated using the proportion of days covered (PDS) and refill gap methods, respectively. Demographic characteristics of patients were obtained. Kaplan-Meier curves with log-rank tests and Cox regression models were used to examine the association between adherence or persistence and time to thrombotic events. RESULTS: A total of 186 patients (mean age: 46.5 ± 12.4 years, females 68.8%) were included in this study. No significant differences were observed in risk factors for thrombosis and cardiovascular diseases among groups. Most patients were adherent (91.4%) and persistent (88.2%) to warfarin treatment. Adherent and persistent patients had a significantly higher rate of thrombotic event-free survival than nonadherent and nonpersistent patients (p < 0.05). Multivariable Cox regression showed that the risk of thrombotic events was higher in nonadherent patients (with a hazard ratio of 3.23 [95% confidence interval CI: 1.15-9.11]) and in nonpersistent patients (with a hazard ratio of 3.45 [95% CI: 1.35-8.82]). CONCLUSIONS: In patients with APS, nonadherence and nonpersistence to warfarin treatment was associated with a higher risk of thrombotic events, suggesting the careful monitoring of those patients.

Prediction of Lifetime Risk of Cardiovascular Disease Deaths Stratified by Sex in the Japanese Population.

Background Lifetime risk is an informative estimate for driving lifestyle and behavioral changes especially for young adults. The impact of composite risk factors for cardiovascular disease on lifetime risk stratified by sex has not been investigated in the Japanese population, which has a much lower mortality of coronary heart disease compared with the Western population. We aimed to estimate lifetime risk of death from cardiovascular disease attributable to traditional risk factors. Methods and Results We analyzed pooled individual data from the Evidence for Cardiovascular Prevention from Observational Cohorts in a Japanese cohort study. A modified Kaplan-Meier approach was used to estimate the remaining lifetime risk of cardiovascular death. In total, 41 002 Japanese men and women with 537 126 person-years of follow-up were included. The lifetime risk at the index-age of 45 years for those with optimal risk factors (total cholesterol <4.65 mmol/L, systolic blood pressure <120 mm Hg, diastolic blood pressure <80 mm Hg, absence of diabetes, and absence of smoking habit) was lower compared with the highest risk profile of ≥2 risk factors (6.8% [95% CI, 0%-11.9%] versus 19.4% [16.7%-21.4%] for men and 6.9% [1.2%-11.5%] versus 15.4% [12.6%-18.1%] for women). Conclusions The magnitude and the number of risk factors were progressively associated with increased lifetime risk even in individuals in early adulthood who tend to have low short-term risk. The degree of established cardiovascular risk factors can be converted into lifetime risk. Our findings may be useful for risk communication in the early detection of future cardiovascular disease risk.

A Combination of Blood Pressure and Total Cholesterol Increases the Lifetime Risk of Coronary Heart Disease Mortality: EPOCH-JAPAN.

AIM: Lifetime risk (LTR) indicates the absolute risk of disease during the remainder of an individual's lifetime. We aimed to assess the LTRs for coronary heart disease (CHD) mortality associated with blood pressure (BP) and total cholesterol levels in an Asian population using a meta-analysis of individual participant data because no previous studies have assessed this risk. METHODS: We analyzed data from 105,432 Japanese participants in 13 cohorts. Apart from grade 1 and 2-3 hypertension groups, we defined "normal BP" as systolic/diastolic BP ＜130/＜80 mmHg and "high BP" as 130-139/80-89 mmHg. The sex-specific LTR was estimated while considering the competing risk of death. RESULTS: During the mean follow-up period of 15 years (1,553,735 person-years), 889 CHD deaths were recorded. The 10-year risk of CHD mortality at index age 35 years was ≤ 0.11%, but the corresponding LTR was ≥ 1.84%. The LTR of CHD at index age 35 years steeply increased with an increase in BP of participants with high total cholesterol levels [≥ 5.7 mmol/L (220 mg/dL)]. This risk was 7.73%/5.77% (95% confidence interval: 3.53%-10.28%/3.83%-7.25%) in men/women with grade 2-3 hypertension and high total cholesterol levels. In normal and high BP groups, the absolute differences in LTRs between the low and high total cholesterol groups were ≤ 0.25% in men and ≤ 0.40% in women. CONCLUSIONS: High total cholesterol levels contributed to an elevated LTR of CHD mortality in hypertensive individuals. These findings could help guide high-risk young individuals toward initiating lifestyle changes or treatments.

Alcohol drinking and brain morphometry in apparently healthy community-dwelling Japanese men.

The clinical implications of alcohol consumption have been extensively examined; however, its effects on brain structures in apparently healthy community-dwellers remain unclear. Therefore, we investigated the relationship between alcohol consumption and brain gray matter volume (GMV) in community-dwelling Japanese men using voxel-based morphometry (VBM). We recruited cognitively intact Japanese men, aged 40-79 years, from a population-based cohort in Shiga, Japan. Brain magnetic resonance imaging was performed, on average, 2 years after demographic and medical information was obtained in 2010-2014. A multivariable linear regression analysis of 639 men was conducted to elucidate the relationship between the amount of alcohol consumed and GMV. VBM statistics were analyzed by threshold-free cluster enhancement with a family-wise error rate of <0.05. The results obtained demonstrated that the amount of alcohol consumed was associated with lower GMV. The VBM analysis showed lower GMV within the parahippocampal, entorhinal, cingulate, insular, temporal, and frontal cortices and cerebellum in very heavy drinkers (≥42 ethanol g/day) than in non-drinkers. Furthermore, alcohol consumption was associated with a higher white matter lesion volume. These results suggest subclinical structural changes similar to alcohol-related neurological diseases.

Protocol and Rationale for the Russian-Japanese "Tackle Obesity and Metabolic Syndrome Outcome by Diet, Activities and Checking Body Weight Intervention" (RJ-TOMODACHI) Randomized Controlled Trial.

Background: The prevalence of obesity in Russia has increased sharply since the mid-1990s. Interestingly, the prevalence of obesity in Japan is lower than in many Western countries. Japan has implemented different types of weight control programs using a smart device to monitor patients remotely. New health promotion methods from Japan are now being used in Russia. The Russian-Japanese "Tackle Obesity and Metabolic Syndrome Outcome by Diet, Activities and Checking Body Weight Intervention" (RJ-TOMODACHI) study aims to evaluate a preventive intervention using Japanese health monitoring technology in reducing excess body weight, compared with standard care, in Russia. Methods and Results: The trial is a single-center, 3-armed, parallel group randomized controlled trial conducted among overweight/obese adults. It has been designed to compare the effectiveness of 2 newly developed interventions against standard care for 6 months. Participants in the low- and high-intensity intervention groups will have 3 and 6 consultations over the study period, respectively. In all, 260 adults were screened at baseline; 65 did not participate in the trial for various reasons. The remaining 195 people were randomized into 3 groups (high-intensity intervention, n=73, low-intensity, n=73; standard care group, n=49). Conclusions: The trial protocol has been designed so that the methodology can be adapted for use in Russia.

Waist Circumference and Domain-Specific Cognitive Function Among Non-Demented Japanese Older Adults Stratified by Sex: Results from the Takashima Cognition Study.

BACKGROUND: While being obese in mid-life is associated with an increased risk of dementia and cognitive decline in late-life, being obese in late-life is shown to be associated with a lower risk of these outcomes in some studies. This phenomenon is known as the "obesity paradox", but the underlying reasons and potential sex difference have not been well understood. OBJECTIVE: To investigate the association between cognition and waist circumference (WC), an alternative measure of body fat which can be measured easier than body mass index (BMI), among older adults in each generation of late-life for men and women separately. METHODS: Three hundred thirty-five participants were used in the current study who were identified by random sampling of residents aged 65-74, 75-84, and 85 + years in Takashima County, Shiga Prefecture, Japan during 2005-2006. Associations between WC and domain-specific cognitive functions measured by 12 neuropsychological tests were examined using multivariable linear regression models with covariates: age, education, and hypertension. RESULTS: Larger WC was associated with better attention/working memory among 65-74-year old women and with better learning/acquisition among 65-74-year-old men, while larger WC was associated with worse learning/acquisition, memory, attention/working memory, and language/fluency among 75-84-year old men. CONCLUSION: We found age and sex differences in the association between WC and domain-specific cognitive functions. Among older old men (age 75-84), larger WC had negative effects on various domains including memory, attention, language, and executive functions, while we did not find any negative effects of larger WC on cognition among women in any age groups.

Industry Perspective of Pediatric Drug Development in the United States: Involvement of the European Union Countries.

BACKGROUND: Efforts to promote the development of pediatric pharmacotherapy include regulatory frameworks and close collaboration between the US Food and Drug Administration and the European Medicines Agency. We characterized the current status of pediatric clinical trials conducted in the United States by the pharmaceutical industry, focusing on the involvement of the European Union member countries, to clarify the industry perspective. METHODS: Data on US pediatric clinical trials were obtained from ClinicalTrials.gov . Binary regression analysis was performed to identify what factors influence the likelihood of involvement of European Union countries. RESULTS: A total of 633 US pediatric clinical trials that met inclusion criteria were extracted and surveyed. Of these, 206 (32.5%) involved a European Union country site(s). The results of binary regression analysis indicated that attribution of industry, phase, disease area, and age of pediatric participants influenced the likelihood of the involvement of European Union countries in US pediatric clinical trials. Relatively complicated or large pediatric clinical trials, such as phase II and III trials and those that included a broad age range of participants, had a significantly greater likelihood of the involvement of European Union countries ( P < .05). CONCLUSION: Our results suggest that (1) the pharmaceutical industry utilizes regulatory frameworks in making business decisions regarding pediatric clinical trials, (2) disease area affects the involvement of European Union countries, and (3) feasibility of clinical trials is mainly concerned by pharmaceutical industry for pediatric drug development. Additional incentives for high marketability may further motivate pharmaceutical industry to develop pediatric drugs.

Isolation and expression of five-amino-acid-deleted variant of feline hepatocyte growth factor (HGF) cDNA.

Hepatocyte growth factor (HGF) is a pleiotropic cytokine that stimulates a wide array of cellular targets, including hepatocytes and other epithelial cells, melanocytes, endothelial and hematopoietic cells. We have cloned a different form of cDNA, with a deletion of 15 base pairs predicted to result in the loss of 5 amino acids from the first kringle domain. To investigate the biological activity, original and deleted variant of feline HGF cDNAs were transiently expressed in COS-7 cells. Both recombinant feline HGFs showed almost the same dose-response curves in the stimulation of the growth of BNL CL.2 cells (a mouse hepatocyte cell line) and scatter activity of Madin-Darby canine kidney (MDCK) cells. The findings reported here suggest that the deleted variant of feline HGF has almost the same biological activity as the original in terms of the proliferation and scatter activity.