Inventory of real-world data sources in Japan: Annual survey conducted by the Japanese Society for Pharmacoepidemiology Task Force.

PURPOSE: The Database Task Force of the Japan Society for Pharmacoepidemiology began its annual surveys of databases available for clinico and pharmacoepidemiological studies in 2010. In this report, we summarize the characteristics of the databases available in Japan based on the results of our 2021 survey to illustrate the recent developments in the infrastructure for database research in Japan. METHODS: We included 20 major databases from the academia, government, or industry that were accessible to third parties. We used a web-based questionnaire to ask the database providers about their characteristics, such as their organization, data source(s), numbers of individuals enrolled, age distribution, code(s) used, and average follow-up periods. RESULTS: We received responses from all 20 databases approached: eight hospital-based databases, six insurer-based databases, four pharmacy-based databases, and two in the "other" category. Among them, 17 contained information from medical claims, pharmacy claims, and/or Diagnosis Procedure Combination data. Most insurer databases contained health check-up data that could be attached to the claims component. Some hospital-based databases had data from electronic medical records. Most insurer-based databases collected data from the insurers of working-age employees and therefore had limited coverage of older people. Most databases coded their medication data using the Japanese reimbursement codes, and many provided Anatomical Therapeutic Chemical Classification codes. CONCLUSIONS: The number of databases available for clinico and pharmacoepidemiological research and the proportion of the population they cover are increasing in Japan. The differences in their characteristics mean that the appropriate database must be selected for a particular study purpose.

Secondary invasive fungal infection in hospitalised patients with COVID-19 in the United States.

BACKGROUND: Invasive fungal infections (IFIs) have been identified as a complication in patients with Coronavirus disease 2019 (COVID-19). To date, there are few US studies examining the excess humanistic and economic burden of IFIs on hospitalised COVID-19 patients. OBJECTIVES: This study investigated the incidence, risk factors, clinical and economic burden of IFIs in patients hospitalised with COVID-19 in the United States. PATIENTS/METHODS: Data from adult patients hospitalised with COVID-19 during 01 April 2020-31 March 2021 were extracted retrospectively from the Premier Healthcare Database. IFI was defined either by diagnosis or microbiology findings plus systemic antifungal use. Disease burden attributable to IFI was estimated using time-dependent propensity score matching. RESULTS: Overall, 515,391 COVID-19 patients were included (male 51.7%, median age: 66 years); IFI incidence was 0.35/1000 patient-days. Most patients did not have traditional host factors for IFI such as hematologic malignancies; COVID-19 treatments including mechanical ventilation and systemic corticosteroid use were identified as risk factors. Excess mortality attributable to IFI was estimated at 18.4%, and attributable excess hospital costs were $16,100. CONCLUSIONS: Invasive fungal infection incidence was lower than previously reported, possibly due to a conservative definition of IFI. Typical COVID-19 treatments were among the risk factors identified. Furthermore, diagnosis of IFIs in COVID-19 patients may be complicated because of the several non-specific shared symptoms, leading to underestimation of the true incidence rate. The healthcare burden of IFIs was significant among COVID-19 patients, including higher mortality and greater cost.

Mirabegron and antimuscarinic use in frail overactive bladder patients in the United States Medicare population.

INTRODUCTION: Overactive bladder (OAB) and frailty are independently associated with patient burden. However, economic burden and treatment-taking behavior have not been well characterized among frail patients with OAB, which, given the varying safety and tolerability profiles of available treatments, is crucial. OBJECTIVES: To assess costs, health care resource utilization, treatment-taking behavior (persistence and adherence) to OAB medication in older, frail OAB patients. METHODS: This was a retrospective cohort study using international business machines MarketScan Medicare Supplemental claims data. Eligible frail patients (per Claims-based Frailty Index score) initiating mirabegron were 1:2 propensity score matched (based on age, sex, and other characteristics) with those initiating antimuscarinics and were followed up to 1 year. All-cause, per-person, per-month costs, health care encounters, persistence (median days to discontinuation assessed using Kaplan-Meier methods) and adherence (≥80% of proportion of days covered at Day 365) were compared. RESULTS: From 2527 patients with incident mirabegron (21%) or antimuscarinic (79%) dispensations, 516 incident mirabegron users (median age: 82 years, 64% female) were matched to 1032 incident antimuscarinic users (median age: 81 years, 62% female). Median cost was higher in mirabegron group ($1581 vs. $1197 per month); this was primarily driven by medication cost. There was no difference in medical encounters. Adherence (39.1% vs. 33.8%) and persistence (103 vs. 90 days) were higher in mirabegron users. CONCLUSIONS: Among frail older adults with OAB, mirabegron use was associated with higher costs and potential improvements in treatment-taking behaviors, particularly with respect to treatment adherence, versus those initiating antimuscarinics.

Estimating the causal effect of transient anemia status on renal and cardiovascular outcomes in community-dwelling patients in Japan at the beginning of impaired renal function using marginal structural modeling.

BACKGROUND: Anemia status may be transient. Causal associations between changes in anemia status over time and adverse outcome development are not well characterized in community-dwelling subjects at the beginning of impaired kidney function. METHODS: This retrospective cohort study used annual health checkup and medical and pharmacy claims data from the JMDC between January 2005 and June 2019. Community-dwelling subjects in Japan with a pre-index estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 followed by a subsequent eGFR < 60 mL/min/1.73 m2 (index) were included. The composite renal outcome was ≥ 30% eGFR reduction over 3 years from baseline, serum creatinine doubling, progression to chronic dialysis, kidney transplantation, or eGFR < 15 mL/min/1.73 m2. The composite cardiovascular outcome was fatal and non-fatal unstable angina, myocardial infarction, heart failure, or cerebrovascular event. Time-dependent anemia risk was evaluated using Breslow's estimator and marginal structural Cox models (MSM). RESULTS: In 32,870 included subjects, 1,396 had anemia at baseline. Adverse outcome incidence was higher in the baseline anemic group, but absolute differences in renal and cardiovascular outcomes between groups were diminished after adjusting for baseline characteristics. In MSM, time-dependent anemia status was associated with higher risk of renal (hazard ratio [95% confidence interval]; 2.6 [1.7-3.8]) and cardiovascular (1.6 [1.2-2.2]) outcomes and mortality (2.8 [1.8-4.3]). Absolute differences in survival probabilities were retained over time but were clinically marginal (1.1-2.7% over 6 years). CONCLUSIONS: Even in subjects at the very early stage of impaired kidney function, early detection and treatment of anemia may help reduce the development of negative sequelae.

Physical oral care prevents ventilator-associated pneumonia in Vietnam: A prospective interventional study.

BACKGROUND: Ventilator-associated pneumonia (VAP) has emerged as a critical issue in the intensive care unit (ICU) because of its high burden on patients and medical staff. Here, we examined the potential for reducing VAP incidence through physical oral care interventions without any medication. METHODS: This prospective interventional study compared VAP incidence during an 8-month baseline period (usual oral care) and a 9-month intervention period (physical oral care with sponge brush) among patients who received mechanical ventilation for >48 h in a tertiary care hospital in Vietnam from 2017 to 2019. Physical oral care was provided by general ICU nurses who had been trained by dentists and infection control nurses. VAP was diagnosed using the Clinical Pulmonary Infection Score. RESULTS: In total, 423 patients were enrolled in the baseline group and 454 patients were enrolled in the intervention group; 303 and 300 patients, respectively, were included in the analysis. Two hundred thirty-eight VAP episodes were identified: 135 (44.6%) during the baseline period and 103 (34.3%) during the intervention period. Univariate analysis revealed significant reduction of VAP occurrence in the intervention period (odds ratio = 0.65; 95% confidence interval = 0.47-0.90; P = 0.010). The incidences of VAP per 1000 ventilator-days were 63.4 (135/2128) during the baseline period and 48.4 (103/2128) during the intervention period (P = 0.038). CONCLUSIONS: Physical oral care without any medication (e.g., chlorhexidine) reduced VAP incidence in the ICU. This method could be used to reduce VAP incidence, particularly in countries with limited medical resources.

Suitability of databases in the Asia-Pacific for collaborative monitoring of vaccine safety.

INTRODUCTION: Information regarding availability of electronic healthcare databases in the Asia-Pacific region is critical for planning vaccine safety assessments particularly, as COVID-19 vaccines are introduced. This study aimed to identify data sources in the region, potentially suitable for vaccine safety surveillance. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE). METHODS: Nineteen countries targeted for database reporting were identified using published country lists and review articles. Surveillance capacity was assessed using two surveys: a 9-item introductory survey and a 51-item full survey. Survey questions related to database characteristics, covariate and health outcome variables, vaccine exposure characteristics, access and governance, and dataset linkage capability. Other questions collated research/regulatory applications of the data and local publications detailing database use for research. RESULTS: Eleven databases containing vaccine-specific information were identified across 8 countries. Databases were largely national in coverage (8/11, 73%), encompassed all ages (9/11, 82%) with population size from 1.4 to 52 million persons. Vaccine exposure information varied particularly for standardized vaccine codes (5/11, 46%), brand (7/11, 64%) and manufacturer (5/11, 46%). Outcome data were integrated with vaccine data in 6 (55%) databases and available via linkage in 5 (46%) databases. Data approval processes varied, impacting on timeliness of data access. CONCLUSIONS: Variation in vaccine data availability, complexities in data access including, governance and data release approval procedures, together with requirement for data linkage for outcome information, all contribute to the challenges in building a distributed network for vaccine safety assessment in the Asia-Pacific and globally. Common data models (CDMs) may help expedite vaccine safety research across the region.

Vasomotor symptoms, sleep problems, and depressive symptoms in community-dwelling Japanese women.

AIM: To assess prevalence and characteristics of vasomotor symptoms in community-dwelling Japanese women. METHODS: These were cross-sectional analyses using data from the National Institute for Longevity Sciences-Longitudinal Study of Aging. The main outcome measures were prevalence and severity of hot flashes and sweating. Associations between hot flashes/sweating (slight, moderate, or severe vs none) and sleep problems were explored using logistic regression, with and without adjustment for age, daily physical activity, and number of urinations/night. Associations between hot flashes/sweating and sleep problems, depressive symptoms, and dietary variables were explored in logistic regression models or general linear models. RESULTS: A total of 1152 women between 40 and 91 years of age were enrolled. Hot flashes were reported by 24.5% of participants; with prevalence and severity highest in those 50-54 years or 2-5 years postmenopause. Sleep problems were reported 15 percentage points more frequently by women who reported hot flashes than by those without hot flashes. Adjusted odds ratios [95% CI] for difficulty in falling asleep and difficulty in sleeping through were 2.09 [1.565-2.796] and 2.07 [1.549-2.763]), respectively. Also, hot flashes were associated with higher risk of depressive symptoms (adjusted odds ratio [95% CI]: 2.99 [2.07-4.32]) and lower life satisfaction, self-esteem, and self-rated health status. A similar pattern was observed in women with and without sweating. No associations were found between hot flashes and dietary factors. CONCLUSIONS: Clear associations were found between hot flashes and sleeping problems, even after adjusting for potential confounding factors. Women who reported hot flashes also reported worse mental and physical health than those who did not report hot flashes.

Thymus and activation-regulated chemokine (TARC/CCL17) predicts decline of pulmonary function in patients with chronic obstructive pulmonary disease.

BACKGROUND: The deterioration of pulmonary function, such as FEV1-decline, is strongly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). However, few investigations shed light on useful biomarkers for predicting the decline of pulmonary function. We evaluated whether thymus and activation-regulated chemokine (TARC), a Th2 inflammation marker, could predict rapid FEV1-decline in COPD patients. METHODS: We recruited 161 patients with stable COPD and performed pulmonary function test once every six months. At the time of registration, blood tests, including serum levels of TARC were performed. We assessed the correlation between changes in parameters of pulmonary function tests and serum levels of TARC. The rapid-decline in pulmonary function was determined using 25th percentile of change in FEV1 or FEV1 percent predicted (%FEV1) per year. RESULTS: In the FEV1-rapid-decline group, the frequency of exacerbations, the degree of emphysema, and serum levels of TARC was higher than in the non-rapid-decline group. When using %FEV1 as a classifier instead of FEV1, age, the frequency of exacerbations, the degree of emphysema and serum levels of TARC in the rapid-decline group was significantly greater than those in the non-rapid-decline group. In univariate logistic regression analysis, TARC was the significant predictive factor for rapid-decline group. In multivariate analysis adjusted for emphysema, serum levels of TARC are independently significant predicting factors for the rapid-decline group. CONCLUSIONS: TARC is an independent predictive biomarker for the rapid-decline in FEV1. Measuring serum TARC levels may help the management of COPD patients by predicting the risk of FEV1 decline.

Effect of Iron Deficiency on a Murine Model of Smoke-induced Emphysema.

Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Smoking susceptibility is important for the onset and development of COPD. We previously reported an association between serum iron concentrations and pulmonary function in male smokers. However, the mechanism governing smoking susceptibility in relation to iron deficiency is unclear; this study aimed to elucidate this mechanism. C57BL/6 male mice were fed an iron-deficient or normal diet and then exposed to cigarette smoke. BAL, histological analysis, and pulmonary function tests were performed after cigarette smoke exposure. Human alveolar type II epithelial A549 cells were treated with an iron chelator. Subsequently, A549 cells were exposed to cigarette smoke extract. In mice exposed to cigarette smoke for 2 weeks, the concentration of alveolar macrophages in the BAL fluid recovered from iron-deficient mice was significantly higher than that in normal diet mice. IL-6 and MCP-1 (monocyte chemotactic protein 1) concentrations in the BAL fluid increased significantly from baseline in iron-deficient mice, but not in normal diet mice. In mice exposed to cigarette smoke for 8 weeks, the pathological mean linear intercepts, physiological total lung capacity, and functional residual capacity in the lungs of iron-deficient mice were significantly greater than in normal diet mice. Phosphorylation of NF-κB was enhanced in the lungs of iron-deficient mice exposed to cigarette smoke and in the iron-chelating A549 cells exposed to cigarette smoke extract. Iron deficiency exaggerated cigarette smoke-induced pulmonary inflammation, suggesting that it may accelerate COPD development.

Switching from intravenous to oral antibiotics in hospitalized patients with community-acquired pneumonia: A real-world analysis 2010-2018.

The Japanese Respiratory Society 2017 guidelines strongly recommend switching from intravenous (IV) to oral antibiotics in patients with community-acquired pneumonia (CAP), following improvement in clinical symptoms and laboratory findings. Here, we retrospectively investigated the real-world, nationwide treatment and switching patterns for hospitalized patients with CAP in Japan using administrative data from 372 Japanese Diagnosis Procedure Combination hospitals from April 2010 to December 2018. Hospitalizations for CAP (patient age ≥20 years) with an A-DROP classification for CAP severity and IV antibiotics initiated on the admission date were included. Overall, 210,314 hospitalizations (moderate CAP: 61.7%) in 183,607 patients were analyzed. The median (interquartile range [IQR]) age at admission was 79 (70-86) years. Penicillin (51.9%) and cephalosporin (38.9%) were the most common IV antibiotic classes used and the median (IQR) duration of IV use was 8 (6-11) days. Switching to oral antibiotics during a hospitalization occurred in 30.1% (n = 63,311) of patients after a median (IQR) of 7 (5-10) days of IV treatment. The most frequently used oral antibiotic classes after a switch were fluoroquinolone (45.9%) and penicillin (24.8%). The switch rate was higher among hospitalizations with milder CAP, in respiratory medicine ward and in larger hospitals. The overall switch rates did not change over the study period. The findings from this analysis suggest that early switch from IV to oral antibiotics was not widely implemented during the 8 years of the study period. Further observation will be needed to see the potential impact of the guidelines update in 2017 in Japan.

Clostridioides (Clostridium) difficile infection in Japanese hospitals 2008-2017: A real-world nationwide analysis of treatment pattern, incidence and testing density.

OBJECTIVE: To characterize treatment pattern, incidence and diagnosis of hospital-onset Clostridioides difficile infection (CDI) in Japan, cases were studied over a 9-year period using a large, administrative database. METHODS: This was a retrospective, cross-sectional analysis of inpatients at 320 Japanese Diagnosis-Procedure Combination (DPC) hospitals. Hospitalizations between April 2008 and March 2017 were extracted for patients aged ≥18 years. CDI was defined as CDI treatment plus CDI diagnosis or positive enzyme immunoassay (EIA) result. Endpoints included treatment (type, route, daily dose, duration), time to CDI onset from admission, and time to recurrence (rCDI) from the end of treatment. Chronological changes were reported for treatment pattern, CDI incidence and EIA testing. RESULTS: The analysis included 11,823 CDI hospitalizations, 1359 with rCDI. Overall, oral metronidazole (MNZ), oral vancomycin (VCM), and intravenous MNZ were used in 50.2%, 42.1% and 1.2% of CDI hospitalizations, respectively. From 2009 to 2017, CDI hospitalizations treated with MNZ more than doubled and VCM more than halved. Median (Q1-Q3) time to CDI and rCDI onset was 25 (11-52) days and 10 (6-17.5) days, respectively. Median treatment duration ranged from 8 to 10 days and median dose was 1 g/day for both MNZ and VCM. CDI incidence remained steady from 2010 until 2017 (0.99/10,000 patient-days) and EIA testing density doubled from 2008 to 2017 (24.46/10,000 patient-days). CONCLUSION: Oral MNZ has become the primary CDI treatment in Japanese DPC hospitals. The treatment duration and dose were aligned to the package insert. CDI diagnostic testing density increased over time, CDI incidence did not. CLINICAL TRIAL REGISTRATION NUMBER: N/A.

Utility of skin perfusion pressure values with the Society for Vascular Surgery Wound, Ischemia, and foot Infection classification system.

OBJECTIVE: The addition of skin perfusion pressure (SPP) might enhance the predictive value of the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system. The purpose of the present study was to evaluate the SPP for each WIfI classification stage among patients with foot wounds by cross-referencing the results of prospectively monitored limb outcomes and to derive the SPP criteria that could be combined with other measurements to grade ischemia for the WIfI classification. METHODS: From July 2015 to June 2017, patients with foot wounds that met the WIfI classification criteria were prospectively enrolled. We assessed the limbs using the WIfI ischemia grade without measuring the transcutaneous oxygen pressure but measured the SPP. After monitoring for 1 year, the predictability of the WIfI stages was analyzed according to whether the limbs had not healed (unchanged or worsened wounds, minor or major amputation, all-cause death) or had healed (improved or healed wounds) by comparing stages 1 and 2 with stages 3 and 4. We also statistically analyzed the SPP values that could be the boundary values between each ischemia grade and reevaluated the predictability of the WIfI stages with the boundary SPP values. RESULTS: We enrolled a total of 91 limbs for 76 patients (mean age, 70.5 ± 12.0 years). The mean SPP values stratified by ischemia grade 0 to 3 were 52.1, 41.1, 27.1, and 18.8 mm Hg, respectively (an SPP of <30 mm Hg indicates severe ischemia). After monitoring for 1 year, 19 of 48 limbs in stage 1 and 2 and 35 of 43 in stage 3 and 4 were in the nonhealed group and 29 limbs in stage 1 and 2 and 8 limbs in stage 3 and 4 were in the healed group. The SPP boundary values between each ischemia (I) grade were calculated as 45 mm Hg for I-0/I-1, 35 for I-1/I-2, and 25 for I-2/I-3. When jointly using the boundary SPP values, the ischemia grade changed for 23 limbs, altering the distribution of the WIfI stages and limb outcomes: 11 of 38 limbs in stage 1 and 2 and 43 of 53 in stage 3 and 4 were transferred to the nonhealed group. The sensitivity, efficiency, and negative predictive value of WIfI staging improved when staging with SPP: from 65% to 80%, 70% to 77%, and 60% to 71%, respectively. CONCLUSIONS: The SPP boundary values that could be used with ischemia grade in the WIfI classification were identified as 45, 35, and 25 mm Hg. The addition of SPP could improve the accuracy of the evaluation.

Passive surveillance of rotavirus gastroenteritis-associated hospitalization using nationwide administrative databases in Japan.

Simple, systematic, and sustainable passive surveillance systems for vaccine-preventable diseases (VPDs) should be useful to quantify the clinical and economic burden in a timely manner with minimum investment. This pilot study evaluated the usefulness of nationwide administrative databases (a hospital-based administrative database and an insurance claims database) for such passive surveillance of children hospitalized for VPDs using rotavirus gastroenteritis (RGE) as an example. Two rotavirus vaccines were launched in November 2011 and July 2012 in Japan. We assessed changes in the proportion of RGE hospitalizations among all-cause hospitalizations (N = 506,524) from the hospital database (April 2008-December 2016) and annual RGE hospitalization rates from the insurance claims database (January 2011-December 2016, n of beneficiaries = 460,585) in children aged <6 years. A total of 12,599 hospitalizations in 12,366 patients were associated with RGE from the hospital database. Similarly, 2038 patients had 2137 RGE-related hospitalizations from the insurance claims database. From 2009 to 2013, the proportion of RGE hospitalizations increased from 2.2% (95% confidence interval, 1.8-2.6) to 3.9% (3.7-4.0), then decreased and remained consistently low from 2014 (1.9% [1.8-2.0]) to 2016 (2.2% [2.1-2.3]). The RGE hospitalization rate decreased sharply in 2014, ranging between 2.85 and 3.52 during 2011-2013 to 0.97 (0.84-1.09) in 2014, and remained low through 2016 (1.18 [1.04-1.32]). In conclusion, we observed changes in RGE hospitalizations over time, without requiring additional data entry by clinicians. Nationwide administrative databases can be useful tools for passive surveillance of VPDs in Japan.

Characterization and risk factors for recurrence of Clostridioides (Clostridium) difficile infection in Japan: A nationwide real-world analysis using a large hospital-based administrative dataset.

OBJECTIVE: Recurrent Clostridioides (Clostridium) difficile infection (rCDI) is common and increases healthcare resource utilization. In this study, we assessed rCDI risk factors using an up-to-date, Japanese national hospital-based database. METHODS: C. difficile infection (CDI) episodes, occurring July 2014-June 2017, in patients aged ≥18 years were extracted from the database and a nested case-control analysis was performed. Cases were defined as rCDI episodes which required re-initiation of oral vancomycin or oral/intravenous metronidazole treatment within 8 weeks from the start of initial treatment. Cases were matched to 4 non-rCDI episodes at the timing of rCDI occurrence. Adjusted odds ratios (ORs) were estimated using multivariate conditional logistic regression model. RESULTS: Of 18,246 initial CDI episodes, 3250 (17.8%) had at least one rCDI. Approximately 90% of episodes occurred in inpatients and 65% were treated with metronidazole. Older age (<75 years vs 75-84 years and vs 85 + years) was associated with higher risk of rCDI (OR = 1.27, 95% confidence interval [1.15, 1.41] and 1.45 [1.30, 1.61], respectively). Use of systemic antibiotics (3.16 [2.90, 3.44]), probiotics (2.53 [2.32, 2.77]), chemotherapy (1.28 [1.08, 1.53]), or proton pump inhibitors (PPIs) (1.17 [1.07, 1.28]), and prior CDI history (1.22 [1.03, 1.43]) were also identified as rCDI risk factors. Vancomycin reduced the risk of rCDI compared with metronidazole treatment (0.83 [0.76, 0.91]). CONCLUSION: This large, multicenter, nationwide study confirmed that older age, PPIs, antibiotics, probiotics, chemotherapy, and prior CDI history are risk factors for rCDI in Japan. There was a 17% decrease of rCDI risk with vancomycin vs metronidazole treatment. CLINICAL TRIAL REGISTRATION NUMBER: N/A.

Anticholinergic burden in the Japanese elderly population: Use of antimuscarinic medications for overactive bladder patients.

OBJECTIVES: To assess anticholinergic use, especially the use of antimuscarinics, in the elderly (aged ≥65 years) Japanese overactive bladder and non-overactive bladder populations. METHODS: Patient records were sourced from a large, nationwide Japanese pharmacy claims database. Anticholinergic use on a random day in 2016 (index date) was investigated through the Anticholinergic Cognitive Burden scale (primary scale), the Anticholinergic Drug Scale, the Anticholinergic Risk Scale and Beers criteria. The prevalence of anticholinergic use and anticholinergic scores at the index date were summarized descriptively. The overactive bladder population was defined as patients who had at least one prescription record for any antimuscarinic (fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin or tolterodine) or the ß3-adrenoreceptor agonist, mirabegron, within the 1-year pre-index period. RESULTS: Among 1 216 126 outpatients, 35 138 (2.9%) were included in the overactive bladder group. In total, 112 (68.7%) of the anticholinergics listed in the scales were identified. In those who received any Anticholinergic Cognitive Burden scale-listed anticholinergic, the mean scores were higher in overactive bladder patients versus non-overactive bladder patients (3.2 ± 1.3 and 1.6 ± 1.1, respectively). Similarly, overactive bladder patients who received antimuscarinics had higher Anticholinergic Cognitive Burden scores (3.3 ± 1.2) than patients who received mirabegron only (1.7 ± 1.1). In 58.8% of the overactive bladder patients, ≥80% of the total Anticholinergic Cognitive Burden score was exclusively attributable to antimuscarinics. CONCLUSIONS: Anticholinergic use was higher in overactive bladder patients versus non-overactive bladder patients. This increased use was largely attributable to antimuscarinics. The alternative use of mirabegron could therefore be considered to reduce the burden experienced by patients in Japan.

MafB enhances the phagocytic activity of RAW264.7 macrophages by promoting Fcgr3 expression.

This study was designed to investigate whether MafB influences the phagocytic activity of macrophages by modulating the expression of the Fc receptors for IgG (FcγRs), Fcgr2b and Fcgr3. In macrophages, FcγRs are critical for the phagocytosis of opsonized pathogens. Of these receptors, Fcgr3 has been shown to play an important role in host defense. As a model to evaluate the mechanism by which MafB influences phagocytosis, we utilized a macrophage cell-line that constitutively expresses a MafB-specific short hairpin (sh)RNA (RAW264.7-MafB-shRNA). Specifically, the levels of Fc receptor mediated-phagocytosis and the levels of FcγRs surface expression were evaluated by flow cytometry analysis, while quantitative real-time PCR analysis was utilized to examine the mRNA expression levels of FcγRs. Compared to the control cell population, RAW264.7-MafB-shRNA cells exhibited significant reductions in Fcgr3 expression and Fc receptor-mediated phagocytosis, but no difference in Fcgr2b expression. Likewise, there was markedly decreased surface expression of Fcgr3 antigen, but not Fcgr2b antigen, in RAW264.7-MafB-shRNA, compared to the control cells. Meanwhile, the observed reduction in the phagocytic activity of the MafB-shRNA-expressing cells was attenuated by ectopic expression of Fcgr3. Together, the results presented here indicate that MafB influences the phagocytic activity of macrophages by promoting Fcgr3, but not Fcgr2b, expression.

Persistence and adherence to overactive bladder medications in Japan: A large nationwide real-world analysis.

OBJECTIVES: To evaluate persistence and adherence to mirabegron and antimuscarinics in Japan using data from two administrative databases. METHODS: The present retrospective study evaluated insurance claims for employees and dependents aged ≤75 years, and pharmacy claims for outpatients. From October 2012 to September 2014, new users of mirabegron or five individual antimuscarinics indicated for overactive bladder in Japan (fesoterodine, imidafenacin, propiverine, solifenacin and tolterodine) were identified and followed for 1 year. Persistence with mirabegron and antimuscarinics were evaluated using Kaplan-Meier methods. Any associations between baseline characteristics (age, sex and previous medication use) and persistence were explored. Adherence was assessed using the medication possession ratio. RESULTS: In total, 3970 and 16 648 patients were included from the insurance and pharmacy claims databases, respectively. Mirabegron treatment was associated with longer median persistence compared with antimuscarinics (insurance claims: 44 [95% confidence intervals 37-56] vs 21 [14-28] to 30 [30-33] days, pharmacy claims: 105 [96-113] vs 62 [56-77] to 84 [77-86] days). The results were consistent when patients were stratified by age, sex and previous medication. Persistence rate at 1 year was higher for mirabegron (insurance claims: 14.0% [11.5-16.8%] vs 5.4% [4.1-7.0%] to 9.1% [5.3-14.2%], pharmacy claims: 25.9% [24.6-27.3%] vs 16.3% [14.0-18.6%] to 21.3% [20.2-22.4%]). Compared with each antimuscarinic, a higher proportion of mirabegron-treated patients had medication possession ratios ≥0.8. CONCLUSIONS: This large nationwide Japanese study shows that persistence and adherence are greater with mirabegron compared with five antimuscarinics.

The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP.

AIMS: Inhibition of vascular smooth muscle cell (VSMC) proliferation by intracellular cAMP prevents excessive neointima formation and hence angioplasty restenosis and vein-graft failure. These protective effects are mediated via actin-cytoskeleton remodelling and subsequent regulation of gene expression by mechanisms that are incompletely understood. Here we investigated the role of components of the growth-regulatory Hippo pathway, specifically the transcription factor TEAD and its co-factors YAP and TAZ in VSMC. METHODS AND RESULTS: Elevation of cAMP using forskolin, dibutyryl-cAMP or the physiological agonists, Cicaprost or adenosine, significantly increased phosphorylation and nuclear export YAP and TAZ and inhibited TEAD-luciferase report gene activity. Similar effects were obtained by inhibiting RhoA activity with C3-transferase, its downstream kinase, ROCK, with Y27632, or actin-polymerisation with Latrunculin-B. Conversely, expression of constitutively-active RhoA reversed the inhibitory effects of forskolin on TEAD-luciferase. Forskolin significantly inhibited the mRNA expression of the pro-mitogenic genes, CCN1, CTGF, c-MYC and TGFB2 and this was reversed by expression of constitutively-active YAP or TAZ phospho-mutants. Inhibition of YAP and TAZ function with RNAi or Verteporfin significantly reduced VSMC proliferation. Furthermore, the anti-mitogenic effects of forskolin were reversed by overexpression of constitutively-active YAP or TAZ. CONCLUSION: Taken together, these data demonstrate that cAMP-induced actin-cytoskeleton remodelling inhibits YAP/TAZ-TEAD dependent expression of pro-mitogenic genes in VSMC. This mechanism contributes novel insight into the anti-mitogenic effects of cAMP in VSMC and suggests a new target for intervention.

cAMP-induced actin cytoskeleton remodelling inhibits MKL1-dependent expression of the chemotactic and pro-proliferative factor, CCN1.

Elevation of intracellular cAMP concentration has numerous vascular protective effects that are in part mediated via actin cytoskeleton-remodelling and subsequent regulation of gene expression. However, the mechanisms are incompletely understood. Here we investigated whether cAMP-induced actin-cytoskeleton remodelling modulates VSMC behaviour by inhibiting expression of CCN1. In cultured rat VSMC, CCN1-silencing significantly inhibited BrdU incorporation and migration in a wound healing assay. Recombinant CCN1 enhanced chemotaxis in a Boyden chamber. Adding db-cAMP, or elevating cAMP using forskolin, significantly inhibited CCN1 mRNA and protein expression in vitro; transcriptional regulation was demonstrated by measuring pre-spliced CCN1 mRNA and CCN1-promoter activity. Forskolin also inhibited CCN1 expression in balloon injured rat carotid arteries in vivo. Inhibiting RhoA activity, which regulates actin-polymerisation, by cAMP-elevation or pharmacologically with C3-transferase, or inhibiting its downstream kinase, ROCK, with Y27632, significantly inhibited CCN1 expression. Conversely, expression of constitutively active RhoA reversed the inhibitory effects of forskolin on CCN1 mRNA. Furthermore, CCN1 mRNA levels were significantly decreased by inhibiting actin-polymerisation with latrunculin B or increased by stimulating actin-polymerisation with Jasplakinolide. We next tested the role of the actin-dependent SRF co-factor, MKL1, in CCN1 expression. Forskolin inhibited nuclear translocation of MKL1 and binding of MKL1 to the CCN1 promoter. Constitutively-active MKL1 enhanced basal promoter activity of wild-type but not SRE-mutated CCN1; and prevented forskolin inhibition. Furthermore, pharmacological MKL-inhibition with CCG-1423 significantly inhibited CCN1 promoter activity as well as mRNA and protein expression. Our data demonstrates that cAMP-induced actin-cytoskeleton remodelling regulates expression of CCN1 through MKL1: it highlights a novel cAMP-dependent mechanism controlling VSMC behaviour.

Prescription sequence symmetry analysis: assessing risk, temporality, and consistency for adverse drug reactions across datasets in five countries.

BACKGROUND: Prescription sequence symmetry analysis (PSSA) is a signal detection method for adverse drug events. Its capacity to consistently detect adverse drug events across different settings has not been tested. We aimed to determine the consistency of PSSA results for detecting positive and negative control adverse drug events across different settings. METHODS: Using a distributed network model, we analyzed prescription dispensing data using PSSA in Australia, Hong Kong, Japan, Korea, and Taiwan. Positive control was amiodarone and thyroxine, as a marker of amiodarone-induced hypothyroidism, a known adverse event with a clear temporal relationship to amiodarone initiation. Negative controls were amiodarone and allopurinol, as a marker of amiodarone-induced gout and thyroxine and allopurinol, as a marker of thyroxine-induced gout. Gout is not recorded as an adverse event in product information for either medicine. Adjusted sequence ratios (ASR) were calculated for each country. Pooled estimates were obtained by using the generic inverse variance method. RESULTS: A positive association was identified between amiodarone and thyroxine in all settings with a pooled ASR 2.63 (95% confidence interval (CI) 1.47-4.72). Temporal analysis showed the effect occurred within the first few weeks of treatment. No significant associations were found for the negative controls in any setting; pooled ASR were 0.76 (95%CI 0.62-0.93) and 0.98 (95%CI 0.85-1.12) for amiodarone-allopurinol and thyroxine-allopurinol, respectively. CONCLUSION: Despite different health settings, different populations, and different patterns of medicine utilization, PSSA gave consistent estimates across countries for a well-known positive association and two negative control adverse events.