Publications by authors named "Tomomi Kimura"

104 Publications

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

J Obstet Gynaecol Res 2021 Jul 18. Epub 2021 Jul 18.

Department of Women's Health, Tokyo Medical and Dental University, Tokyo, Japan.

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.
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http://dx.doi.org/10.1111/jog.14937DOI Listing
July 2021

The Costs and Healthcare Resource Utilization Associated with Anticholinergic Burden in Long-Stay Nursing Home Residents with Overactive Bladder in the US.

Pharmacoecon Open 2021 Jul 13. Epub 2021 Jul 13.

Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Health and Biomedical Sciences Building 2, Office 4052, 4849 Calhoun Road, Houston, TX, 77204-5047, USA.

Background: Overactive bladder (OAB) is a prevalent condition commonly treated with anticholinergic medications. The extent to which anticholinergic burden is associated with costs and healthcare resource use (HCRU) in the long-stay nursing home (LSNH) setting is currently unknown.

Objectives: This research evaluated the impact of anticholinergic burden on HCRU and related costs among LSNH residents with OAB.

Methods: This was a cohort study based on 2013-2015 Minimum Data Set-linked Medicare claims data involving LSNH residents aged ≥ 65 years with OAB and having Parts A, B and D coverage 6 months pre- and ≥ 12 months post-nursing home admission date (index date). Cumulative anticholinergic burden was determined using the Anticholinergic Cognitive Burden scale and defined daily dose. Direct medical costs related to HCRU were examined. HCRU included inpatient, outpatient, emergency room (ER), and physician office visits. Costs and HCRU associated with levels of anticholinergic burden were evaluated using generalized linear models.

Results: A total of 123,308 LSNH residents with OAB were included in this study. Most residents (87.2%) had some level (12.8%, none; 18.0%, low; 41.9%, moderate; and 27.3%, high) of cumulative anticholinergic burden. Results indicate that all types of resource utilization were higher among those with any level of anticholinergic burden than those with no burden. The outpatient, ER, and physician costs tended to be higher with increasing anticholinergic burden.

Conclusions: Costs and HCRU patterns reflected increasing trends with anticholinergic burden. Targeted efforts towards reducing anticholinergic burden among LSNH residents with OAB may result in decreases in costs and HCRU.
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http://dx.doi.org/10.1007/s41669-021-00281-8DOI Listing
July 2021

The Incidence and Risk Analysis of Lung Cancer Development in Patients with Chronic Obstructive Pulmonary Disease: Possible Effectiveness of Annual CT-Screening.

Int J Chron Obstruct Pulmon Dis 2021;16:739-749. Epub 2021 Mar 25.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan.

Purpose: Lung cancer is a serious complication in patients with chronic obstructive pulmonary disease (COPD) and accounts for approximately 15% of deaths in patients with COPD. However, with the exception of emphysema, few reports to date have been published on the factors that predict lung cancer development in COPD patients. It has been reported that patients with COPD develop lung cancer at a rate of 0.8% - 1.7%/year, but the incidence may be higher in the Japanese population. Therefore, we investigated the incidence of lung cancer and the lung cancer mortality rate in Japanese COPD patients, as well as factors that are associated with the development of lung cancer in COPD patients.

Patients And Methods: We followed up 224 patients with stable COPD and performed CT examinations at least once per year. The incidence of lung cancer was recorded and data at enrollment were compared with data of the group that did not develop lung cancer.

Results: Over a median follow-up period of 4.58 years, lung cancer was newly diagnosed in 19 patients; the incidence of lung cancer in this population was 1.85%/year. Patients who developed lung cancer had more severe emphysema assessed by CT and GOLD classification and were more likely to be current smokers than those who did not develop lung cancer. No other significant differences were observed between these two groups. Mortality was significantly increased in patients who developed lung cancer compared with those who did not.

Conclusion: In COPD patients, the incidence of lung cancer is higher and the development of lung cancer worsens the prognosis; however, lung cancer development is unpredictable and attention should be paid to all patients. Annual CT screening is important for early detection of lung cancer.
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http://dx.doi.org/10.2147/COPD.S287492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006963PMC
June 2021

Prevalence and Factors Associated with Cumulative Anticholinergic Burden Among Older Long-Stay Nursing Home Residents with Overactive Bladder.

Drugs Aging 2021 Apr 8;38(4):311-326. Epub 2021 Mar 8.

Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Houston, TX, USA.

Background: Overactive bladder (OAB), the primary cause of urinary incontinence in nursing homes, is commonly treated with anticholinergic medications; however, the elderly population is vulnerable to the adverse effects associated with anticholinergic burden. Given the relatively high prevalence of OAB among nursing home residents, it is important to understand the magnitude of anticholinergic burden in this population.

Objectives: The objectives of this study were to (1) examine the prevalence of cumulative anticholinergic burden among long-stay nursing home (LSNH) residents with OAB; and (2) identify the factors associated with varying levels of cumulative anticholinergic burden.

Methods: This was a retrospective, cohort study using Minimum Data Set-linked Medicare claims data. Anticholinergic burden was determined based on the Anticholinergic Cognitive Burden scale and patient-specific dosing using defined daily dose. The Andersen Behavioral Model framework was used to identify the predisposing, enabling, and need factors associated with levels of anticholinergic burden. Multivariable logistic regression models were developed to determine the factors associated with levels of anticholinergic burden.

Results: A total of 123,308 LSNH residents with OAB were identified; 87.2% had some degree of anticholinergic burden and 27.3% had high cumulative burden. Multiple factors were associated with higher levels of burden, including younger age, female sex, and non-Hispanic White ethnicity (predisposing factors); dual eligibility, Southern geographic region, and rural residence (enabling factors); and a number of comorbidities and concomitant medications (need factors).

Conclusions: This study revealed a high level of anticholinergic burden among LSNH residents. Multiple factors were associated with a high level of burden. There is a need to optimize the use of anticholinergics due to their significant safety concerns in the LSNH setting.
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http://dx.doi.org/10.1007/s40266-021-00833-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007511PMC
April 2021

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

Pharmacoepidemiol Drug Saf 2021 07 23;30(7):843-857. Epub 2021 Mar 23.

Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.

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.
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http://dx.doi.org/10.1002/pds.5214DOI Listing
July 2021

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

Allergol Int 2021 Jan 20;70(1):81-88. Epub 2020 May 20.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan.

Background: The deterioration of pulmonary function, such as FEV-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 FEV-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 FEV or FEV percent predicted (%FEV) per year.

Results: In the FEV-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 %FEV as a classifier instead of FEV, 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 FEV. Measuring serum TARC levels may help the management of COPD patients by predicting the risk of FEV decline.
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http://dx.doi.org/10.1016/j.alit.2020.04.004DOI Listing
January 2021

Diagnosis Patterns of CKD and Anemia in the Japanese Population.

Kidney Int Rep 2020 May 10;5(5):694-705. Epub 2020 Apr 10.

Medical Affairs, Astellas Pharma Inc., Tokyo, Japan.

Introduction: Although early intervention for chronic kidney disease (CKD) and renal anemia are desirable, these conditions are often asymptomatic during their early stages and may be underdiagnosed.

Methods: We retrospectively analyzed Japanese administrative claims data for general and hospital populations. The data period for the general and hospital data ranged from January 2011 to December 2016 and from April 2008 to July 2017, respectively. CKD stage was determined by estimated glomerular filtration rate (eGFR). Anemia was defined per Japanese guidelines using hemoglobin (Hb) values. The proportion of patients who had eGFR-defined stages G3-G5 CKD without a CKD diagnosis, and Hb-defined anemia without an anemia diagnosis or treatment records, was estimated.

Results: Among 16,779 (general) and 68,161 (hospital) patients, a high proportion of G3 CKD patients did not have a CKD-related diagnosis (general: G3a, 95.0%; G3b, 68.4%; hospital: G3a, 89.2%; G3b, 67.9%); however, some patients were treated with antihypertensives. Among anemic patients, 75.7% (G3a) and 66.7% (G3b) of the general population, and 56.2% (G3a) and 47.5% (G3b) of the hospital population, did not have an anemia-related diagnosis or treatment. CKD and anemia were more likely to be diagnosed in patients with G4 and G5 CKD.

Conclusion: A high proportion of G3 CKD patients did not have a CKD-related diagnosis. Likewise, many anemic patients with G3 CKD did not have an anemia-related diagnosis. Despite the lack of a CKD-related diagnosis, some patients received appropriate treatment (e.g., antihypertensives). Further outreach to CKD and anemia patients at earlier stages may be warranted.
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http://dx.doi.org/10.1016/j.ekir.2020.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210702PMC
May 2020

[The Effect of Patient Age on Anticholinergic Use in the Elderly Japanese Population -Differences between Four Anticholinergic Scales].

Yakugaku Zasshi 2020 ;140(5):701-710

Department of Urology, National Center for Geriatrics and Gerontology.

We previously reported that anticholinergic (AC) drug use increases with age in the elderly Japanese population. In this analysis, we investigated attribution for each AC drug type to total AC burden using different elderly age groups. Prescription records (from 09/23/2015 to 12/31/2016) for outpatients using any AC were extracted from pharmacy claims (primary source) and hospital-based databases. AC burden (number of AC drugs and AC score) and AC type were assessed using the Anticholinergic Cognitive Burden (ACB) scale, Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Beers criteria. Age was categorized using three subgroups (65-74, 75-84, and ≥85 years). Overall, 125426, 140634, 35628, and 23149 of the pharmacy outpatients received ≥1 AC drug from the ACB scale, ADS, ARS, or Beers criteria, respectively. The number of AC drugs increased with age for the ACB scale and ADS groups; but decreased for the ARS and Beers criteria. Antihypertensives provided the biggest contribution to AC score using the ACB scale and ADS, and antihistamines for the ARS. Proportional attribution to AC score typically increased with age for antihypertensives (ADS highest proportion: 34.6% for ≥85 years) and cardiac agents, but decreased for antihistamines (ARS lowest proportion: 15.3% for ≥85 years), corticosteroids, and antiepileptics. Similar findings were typically observed for the hospital database. In conclusion, antihypertensives were the principal type of AC drugs using the ACB scale and ADS and their attribution to AC score increased with age. Antihistamines were the principal drug type for the ARS.
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http://dx.doi.org/10.1248/yakushi.19-00229DOI Listing
September 2020

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

J Infect Chemother 2020 Jul 10;26(7):706-714. Epub 2020 Apr 10.

Advanced Informatics and Analytics, Astellas Pharma Inc., 2-5-1 Nihonbashi Honcho, Chuo-ku, Tokyo, 103-8411, Japan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jiac.2020.03.010DOI Listing
July 2020

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

J Infect Chemother 2020 May 17;26(5):438-443. Epub 2020 Feb 17.

Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8411, Japan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jiac.2019.11.005DOI Listing
May 2020

E-selectin as a prognostic factor of patients hospitalized due to acute inflammatory respiratory diseases: a single institutional study.

EXCLI J 2019 11;18:1062-1070. Epub 2019 Nov 11.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan.

When examining patients with acute inflammatory respiratory diseases, it is difficult to distinguish between infectious pneumonia and interstitial pneumonia and predict patient prognosis at the beginning of treatment. In this study, we assessed whether endothelial selectin (E-selectin) predicts the outcome of patients with acute inflammatory respiratory diseases. We measured E-selectin serum levels in 101 patients who were admitted to our respiratory care unit between January 2013 and December 2013 because of acute inflammatory respiratory diseases that were eventually diagnosed as interstitial pneumonia (n = 38) and lower respiratory tract infection (n = 63). Seven of these patients (n = 101) died. The pneumonia severity score was significantly higher and the oxygen saturation of arterial blood measured by pulse oximeter (SpO)/fraction of inspiratory oxygen (FiO) was significantly lower in the deceased patients than in the surviving patients. There were significantly fewer peripheral lymphocytes and significantly higher E-selectin serum levels in the deceased patients than in the surviving patients. In the multiple logistic regression analysis, the E-selectin serum levels and SpO/FiO ratio were independent predictive factors of prognosis. The risk of death during acute respiratory disease was determined using a receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) was 0.871 as calculated from the ES, and the cutoff value was 6453.04 pg/ml, with a sensitivity of 1.00 and a specificity of 0.72 (p = 0.0027). E-selectin may be a useful biomarker for predicting the prognosis of patients with acute inflammatory respiratory diseases.
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http://dx.doi.org/10.17179/excli2019-1624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909376PMC
November 2019

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

Am J Respir Cell Mol Biol 2020 05;62(5):588-597

Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan.

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.
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http://dx.doi.org/10.1165/rcmb.2018-0239OCDOI Listing
May 2020

Drug Utilization Patterns in Patients with Diabetes Initiating Sodium Glucose Co-Transporter-2 Inhibitors (SGLT2i) in Japan: A Multi-Database Study (2014-2017).

Diabetes Ther 2019 Dec 18;10(6):2233-2249. Epub 2019 Oct 18.

Astellas Pharma Inc., 5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8411, Japan.

Introduction: This study aimed to identify drug utilization patterns in patients initiating sodium glucose co-transporter-2 inhibitors (SGLT2i) in the first 3 years of their launch in Japan.

Methods: This was a retrospective study using three administrative databases in Japan: a pharmacy claims database, a hospital-based database, and an insurance claims database. Prescription data were extracted from adult outpatients with diabetes who started SGLT2i between April 2014 and March 2017 to evaluate pre-index and concomitant medications. For glimepiride and insulin co-users, dose at SGLT2i add-on was also assessed.

Results: Data from a total of 14,861 patients in the pharmacy dataset (P-dataset), 27,039 in the hospital dataset (H-dataset), and 12,408 in the insurance dataset (I-dataset) were analyzed. The majority of SGLT2i new users (ca. 70%) were taking one to three concomitant antidiabetic medications. Around half of SGLT2i initiators used dipeptidyl peptidase 4 inhibitors and/or biguanides before using SGLT2i or concomitantly with SGLT2i. The average daily glimepiride dose decreased from 2.1 mg/day during the pre-index period to 1.8 mg/day at SGLT2i add-on in the P-dataset and from 1.9 to 1.7 mg/day in the both H- and I-datasets, respectively, with a decreasing trend observed during the first 3 years of launch. The average daily insulin dose at SGLT2i add-on was higher during the first 15 months of launch and then decreased thereafter. Nearly 40% or more SGLT2i new users were taking at least five concomitant medications: cardiovascular agents were predominantly co-prescribed.

Conclusion: SGLT2i were frequently used as second- or later-line treatment and as part of a dual, triple, or quadruple regimen, as well as co-prescribed with many other medications in the first 3 years of their launch. For SGLT2i users taking concomitant SU or insulin medications, the average daily doses of SU and insulin at SGLT2i add-on decreased slightly over the study period.

Funding: Astellas Pharma Inc., Tokyo, Japan.
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http://dx.doi.org/10.1007/s13300-019-00710-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848432PMC
December 2019

Real-World Effectiveness of Sodium Glucose Co-Transporter-2 Inhibitors in Japanese Patients with Diabetes Mellitus.

Diabetes Ther 2019 Dec 15;10(6):2219-2231. Epub 2019 Oct 15.

Astellas Pharma Inc., Tokyo, Japan.

Introduction: Sodium glucose co-transporter-2 inhibitors (SGLT2i) have been on the market for 5 years in Japan. We explored the real-world effectiveness of SGLT2i in Japan.

Methods: We retrospectively analyzed two large Japanese administrative databases from JMDC Inc.: insurance-dataset (I-dataset) and Medical Data Vision Co. Ltd. [hospital-dataset (H-dataset)]. Patients who newly started SGLT2i or other oral antidiabetic drugs (OADs) between 1 April 2014 and 31 March 2016 were selected for this analysis and followed for 1 year from the index date. Changes in glycated hemoglobin (HbA1c), body mass index (BMI), and estimated glomerular filtration rate (eGFR) were evaluated during the 1-year period.

Results: A total of 127,961 patients in the H-dataset and 26,436 in the I-dataset were included in this analysis. Baseline HbA1c, BMI, and eGFR levels tended to be higher in SGLT2i users than in other OAD cohorts. After 1 year, 44.3% (I-dataset) and 53.3% (H-dataset) of SGLT2i users and 33.0-44.2% (I-dataset) and 47.0-58.1% (H-dataset) of other users were still on their medications. The mean HbA1c level decreased by - 0.7 to - 0.9% in SGLT2i users versus - 0.4 to - 1.5% in the other cohorts. The mean BMI decreased by - 0.8 kg/m in SGLT2i users whereas the change in other cohorts was - 0.5 to 0.4 kg/m. No clinically relevant changes in eGFR were observed over the period.

Conclusion: This study showed that around half of the SGLT2i users were still on medication after 1 year from treatment initiation. Initiation of SGLT2i was associated with improvement in HbA1c and BMI, with no abnormal changes in renal function observed in the first year following treatment. These findings support the results from clinical trials and will expand the existing evidence of SGLT2i use in real-life practice in Japan.

Funding: Astellas Pharma Inc., Tokyo, Japan.
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http://dx.doi.org/10.1007/s13300-019-00708-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848551PMC
December 2019

Technical note: improved positioning protocol for patient setup accuracy in conventional radiotherapy for lung cancer.

Radiol Phys Technol 2019 Dec 23;12(4):426-432. Epub 2019 Sep 23.

Department of Radiation Therapy, Hirosaki Central Hospital, 3-1 Yoshino-cho, Hirosaki, Aomori, 036-8188, Japan.

This study aimed to investigate an improved setup protocol for maintaining patient setup accuracy, with minimal or no use of image-guided radiation therapy in conventional radiotherapy for lung cancer. A coordinate value for the treatment couch in the anterior-posterior (AP) direction was obtained from the first fraction using bony anatomy image guidance. The coordinate value was invariably used for patient positioning in the second and subsequent treatment fractions. The errors of 2410 setup image sets (anterior and lateral) from 105 patients with lung cancer were analyzed. The systematic and random patient positioning errors in the AP direction were 0.6 ± 1.0 mm. Such errors accounted for 97% of all fractions within ± 2 mm. The protocol resulted in minimal patient setup errors in the AP direction using only one image for guidance; therefore, it may be applied to conventional radiotherapy for lung cancer in case of insufficient image guidance.
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http://dx.doi.org/10.1007/s12194-019-00537-3DOI Listing
December 2019

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

J Vasc Surg 2019 10 18;70(4):1308-1317. Epub 2019 May 18.

Department of Plastic and Reconstructive Surgery, Kawasaki Medical School, Kurashiki, Japan.

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.
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http://dx.doi.org/10.1016/j.jvs.2019.01.045DOI Listing
October 2019

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.

J Infect Chemother 2019 Aug 12;25(8):615-620. Epub 2019 Apr 12.

Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8411, Japan.

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.
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http://dx.doi.org/10.1016/j.jiac.2019.03.011DOI Listing
August 2019

Characteristics of Patients with Diabetes Initiating Sodium Glucose Co-transporter-2 Inhibitors (SGLT2i): Real-World Results from Three Administrative Databases in Japan.

Diabetes Ther 2019 Apr 7;10(2):549-562. Epub 2019 Feb 7.

Astellas Pharma Inc., Tokyo, Japan.

Introduction: The aim of this study was to evaluate the characteristics of new users of sodium glucose co-transporter-2 inhibitors (SGLT2i) in comparison with those of new users of other oral antidiabetic drugs (OADs) using data retrieved from three administrative databases in Japan.

Methods: This study included adult patients from each database who started an OAD between 2014 and 2017. Outpatients who started SGLT2i therapy were included in the SGLT2i cohort. The remaining outpatients were grouped according to the OAD class of their earliest initial prescription after no use of the index OAD during the 6-month pre-index period. Diabetes-related complications were evaluated using the Diabetes Complication Severity Index.

Results: In total, 176,355 patients in the hospital-based administrative database (H-dataset), 98,361 in the pharmacy claims database (P-dataset) and 37,786 in the insurance claims database (I-dataset) were analyzed. In the H-dataset, SGLT2i users, compared with users of other OADs, tended to be younger (mean age at index: 57.7 vs. 60.3-69.2 years) and to have a higher prevalence of hypercholesterolemia (73.5 vs. 55.2-71.4%), a higher mean body weight (74.4 vs. 60.5-70.8 kg), a higher body mass index (27.6 vs. 23.5-26.4 kg/m) and a higher glycated hemoglobin level (8.4 vs. 7.4-8.1%). There were no distinct differences in the prevalence of complications between SGLT2i users and users of other OADs in the H-dataset. Similar trends were noted in the other datasets.

Conclusion: Patients initiating SGLT2i therapy differed in several characteristics from new users of other OADs. SGLT2i were prescribed more frequently to younger patients, those at increased cardiovascular risk or those with poorer glycemic control.

Funding: Astellas Pharma Inc., Tokyo, Japan.
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http://dx.doi.org/10.1007/s13300-019-0577-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437244PMC
April 2019

Smaller erector spinae muscle size is associated with inability to recover activities of daily living after pneumonia treatment.

Respir Investig 2019 Mar 11;57(2):191-197. Epub 2018 Dec 11.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. Electronic address:

Background: Elderly patients who are hospitalized due to pneumonia experience deterioration of their activities of daily living (ADL) during this period; in some cases, this loss of ADL is not recovered at the end of antibiotic treatment. In this study, we examined whether erector spinae muscle cross-sectional area (ESMCSA) measured by computed tomography (CT) could predict a low level of ADL at the end of antibiotic treatment for pneumonia.

Methods: Eighty patients (mean age 74.8 years) with pneumonia, who were admitted to Yamagata university hospital between 2015 and 2016, were analyzed retrospectively. In all cases, chest CT was performed on admission and ESMCSA was measured at the level of the 12th thoracic vertebra. Patient levels of ADL were also measured, both on admission and at the end of treatment, using the Barthel Index.

Results: Patients with lower levels of ADL at the end of treatment were significantly older and tended to have a lower body mass index, poorer nutritional status, and more severe pneumonia than did patients who were self-reliant. Significantly smaller ESMCSAs were noted in patients who required assistance at the end of treatment than in those who were self-reliant. In multivariate logistic regression analysis, smaller ESMCSA was significantly associated with a lower level of ADL at the end of treatment, independent of age, sex, severity of pneumonia, nutritional status, or dehydration status.

Conclusion: These results suggest that ESMCSA can predict ADL level after antibiotic treatment of pneumonia.
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http://dx.doi.org/10.1016/j.resinv.2018.11.002DOI Listing
March 2019

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

J Infect Chemother 2019 Mar 27;25(3):175-181. Epub 2018 Nov 27.

Kawasaki City Institute for Public Health, 3-25-13 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-0821, Japan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jiac.2018.11.003DOI Listing
March 2019

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

Int J Urol 2018 10 1;25(10):855-862. Epub 2018 Aug 1.

Astellas Pharma Inc., Tokyo, Japan.

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 β3-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.
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http://dx.doi.org/10.1111/iju.13758DOI Listing
October 2018

Spindle Cell Lipoma of the Thumb.

Plast Reconstr Surg Glob Open 2018 Feb 9;6(2):e1671. Epub 2018 Feb 9.

Department of Plastic and Reconstructive Surgery, Kawasaki Medical School, Okayama, Japan.

We report the case of a 34-year-old man who presented with a 4-year history of a soft tissue on the palmar aspect of the thumb. Magnetic resonance imaging demonstrated the presence of a mass with heterogeneous high intensities on T1-weighted images and high intensities on T2-weighted images. We performed excisional biopsy. Histologically, the tumor was composed of mature adipocytes and spindle cells in a collagen background. Immunohistochemically, the tumor cells showed strong expression of CD34. Therefore, we diagnosed it as spindle cell lipoma. To the best of our knowledge, only 2 cases of spindle cell lipoma of the thumb have previously been reported.
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http://dx.doi.org/10.1097/GOX.0000000000001671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865930PMC
February 2018

Dual Role of CREB in The Regulation of VSMC Proliferation: Mode of Activation Determines Pro- or Anti-Mitogenic Function.

Sci Rep 2018 03 20;8(1):4904. Epub 2018 Mar 20.

Translational Health Sciences, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.

Vascular smooth muscle cell (VSMC) proliferation has been implicated in the development of restenosis after angioplasty, vein graft intimal thickening and atherogenesis. We investigated the mechanisms underlying positive and negative regulation of VSMC proliferation by the transcription factor cyclic AMP response element binding protein (CREB). Incubation with the cAMP elevating stimuli, adenosine, prostacyclin mimetics or low levels of forksolin activated CREB without changing CREB phosphorylation on serine-133 but induced nuclear translocation of the CREB co-factors CRTC-2 and CRTC-3. Overexpression of CRTC-2 or -3 significantly increased CREB activity and inhibited VSMC proliferation, whereas CRTC-2/3 silencing inhibited CREB activity and reversed the anti-mitogenic effects of adenosine A2B receptor agonists. By contrast, stimulation with serum or PDGF significantly increased CREB activity, dependent on increased CREB phosphorylation at serine-133 but not on CRTC-2/3 activation. CREB silencing significantly inhibited basal and PDGF induced proliferation. These data demonstrate that cAMP activation of CREB, which is CRTC2/3 dependent and serine-133 independent, is anti-mitogenic. Growth factor activation of CREB, which is serine-133-dependent and CRTC2/3 independent, is pro-mitogenic. Hence, CREB plays a dual role in the regulation of VSMC proliferation with the mode of activation determining its pro- or anti-mitogenic function.
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http://dx.doi.org/10.1038/s41598-018-23199-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861041PMC
March 2018

Heart-type fatty acid binding protein as a prognostic factor in patients with exacerbated chronic obstructive pulmonary disease.

Respir Investig 2018 Mar 19;56(2):128-135. Epub 2017 Dec 19.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan; Department of Pulmonary Medicine, Fukushima Medical University School of Medicine, 1 Hikariga-Oka, Fukushima 960-1295, Japan. Electronic address:

Background: The designation of some cardiac-specific proteins as prognostic biomarkers in chronic obstructive pulmonary disease (COPD) exacerbations suggest that the process of exacerbation involves cardiomyocyte injury. Among these cardiac biomarkers, heart-type fatty acid binding protein (h-FABP) is considered a very sensitive diagnostic marker for cardiomyocyte injury and a prognostic marker in chronic heart failure. However, the prognostic usefulness of h-FABP in patients with COPD remains unclear.

Methods: Sixty-six patients were enrolled in this study. Subjects who recovered from COPD exacerbation and were discharged without needing home oxygen therapy were defined as the improved group. Those who died of the COPD exacerbations, were discharged but needed home oxygen therapy, or were transferred to a rehabilitation hospital for respiratory failure and the remaining aftereffects of exacerbation were defined as the unimproved group.

Results: The improved and unimproved groups included 54 and 12 subjects, respectively. Compared with the improved group, the unimproved group had significantly higher white blood cell counts and alanine aminotransferase, lactate dehydrogenase, blood urea nitrogen (BUN), uric acid, potassium, and h-FABP levels, and significantly lower total protein and total cholesterol levels and estimated glomerular filtration rates, either at admission or during the early morning within 24h after admission. A multivariate analysis revealed that higher serum h-FABP and potassium levels were independently predictive of a poor prognosis following a COPD exacerbation, and a receiver operating characteristic curve analysis yielded a cutoff of 4.5ng/ml for predicting lack of improvement.

Conclusion: H-FABP may predict the outcomes of COPD exacerbation.
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http://dx.doi.org/10.1016/j.resinv.2017.11.010DOI Listing
March 2018

Impact of cigarette smoking on decline in forced expiratory volume in 1s relative to severity of airflow obstruction in a Japanese general population: The Yamagata-Takahata study.

Respir Investig 2018 Mar 24;56(2):120-127. Epub 2017 Dec 24.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. Electronic address:

Background: Few studies are available regarding the annual decline of forced expiratory volume in 1s (FEV1) in chronic obstructive pulmonary disease patients with mild airflow obstruction. This study sought to clarify to what extent cigarette-smoking individuals with mild airflow obstruction lose pulmonary function annually.

Methods: From 2004 to 2006, pulmonary function tests were performed on people >40 years of age, during the annual health checkup held in Takahata, Yamagata, Japan (initial study population, n=3253). In 2011, pulmonary function tests were performed again on participants who agreed to undergo reexamination (follow-up study population, n=838).

Results: Smokers have decreased pulmonary function in terms of percent forced vital capacity (FVC), %FEV1, and FEV1/FVC; the stages of airflow obstruction were also more severe in smokers than never-smokers. The annual decline in FEV1 was significantly greater in smokers than in never-smokers. The median annual decline in FEV1 was most significant in individuals with mild airflow obstruction. The annual decline in FEV1 was greater in smokers with mild airflow obstruction than in smokers with moderate airflow obstruction. In analyzing the decline in %FEV1, the annual change in smokers with mild airflow obstruction was greater than that in smokers with normal spirometric values.

Conclusion: The annual decline in FEV1 was most significant in smokers with mild airflow obstruction in a Japanese general population. This highlights the importance of early detection of chronic obstructive pulmonary disease patients among the general population in order to prevent disease progression in undiagnosed patients.
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http://dx.doi.org/10.1016/j.resinv.2017.11.011DOI Listing
March 2018

The Epidemiology of Clostridium difficile Infection in Japan: A Systematic Review.

Infect Dis Ther 2018 Mar 13;7(1):39-70. Epub 2018 Feb 13.

Astellas Pharma, Inc., Tokyo, Japan.

To increase understanding of the epidemiology, risks, consequences and resource utilization of Clostridium difficile infection (CDI) in Japan, a systematic literature review was undertaken of relevant publications from January 2006 to November 2017. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and methods, 55 articles met the criteria for full review. The majority (58%) of studies were from a single site, with the most recent data from 2015. The incidence, reported prevalence and recurrence rate of CDI in Japan were 0.8-4.71/10,000 patient-days, 0.3-5.5/1000 patients and 3.3-27.3%, respectively, and varied according to setting, population, CDI definition and detection method. Most C. difficile isolates associated with CDI in Japan were toxin A+B+, with a low level of C. difficile binary toxin-positive (CDT+) strains (0-6.8% reported across studies). The most common C. difficile PCR ribotypes associated with infection in Japan were smz/018, 002, 052 and 369. Data regarding the impact of CDI on length of hospital stay were limited. Reported all-cause mortality in patients with CDI ranged from 3.4 to 15.1% between 2007 and 2013. Two studies assessed risk factors for CDI recurrence, identifying malignant disease, intensive care unit hospitalization and use of proton pump inhibitors as factors increasing the risk of initial and/or recurrent CDI. No study analyzed initial CDI treatment in relation to recurrence. More comprehensive surveillance and coordinated studies are needed to map trends, understand risk factors, and recognize the extent and impact of CDI in Japanese patients.

Funding: Astellas Pharma, Inc. Plain language summary available for this article.
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http://dx.doi.org/10.1007/s40121-018-0186-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840105PMC
March 2018

Prevalence of diabetes mellitus in individuals with airflow obstruction in a Japanese general population: The Yamagata-Takahata Study.

Respir Investig 2018 Jan 7;56(1):34-39. Epub 2017 Dec 7.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. Electronic address:

Background: Diabetes has been reported as a comorbidity of chronic obstructive pulmonary disease (COPD) in Western countries, but it has not been demonstrated in epidemiological reports in Japan. The purpose of this study was to clarify whether the relationship between airflow obstruction and diabetes can be confirmed in a Japanese general population.

Methods: From 2004 to 2006, blood sampling and pulmonary function tests were performed on 3045 people over the age of 40 years in annual health check-ups held in Takahata, Yamagata Prefecture, Japan. Pulmonary function was re-evaluated in 2009 and 2011.

Results: The prevalence of diabetes did not differ between subjects with and without airflow obstruction. Furthermore, although body mass index decreased, no increase in the prevalence of diabetes was observed with the progression of airflow obstruction. The annual changes in forced expiration volume in 1s (FEV1) did not differ depending on the presence or absence of diabetes in the study population.

Conclusion: There was no difference in the prevalence of diabetes between subjects with airflow obstruction and those without. As patients with COPD in Japan are thinner than in the West, diabetes may not be a common comorbidity in Japanese patients with COPD.
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http://dx.doi.org/10.1016/j.resinv.2017.11.003DOI Listing
January 2018

Anatomical Analysis of Cutaneous Perforator Distribution in the Forearm.

Plast Reconstr Surg Glob Open 2017 Oct 26;5(10):e1550. Epub 2017 Oct 26.

Department of Plastic and Reconstructive Surgery, Kawasaki Medical School, Kurashiki, Japan.

Background: Few reports describe the distribution of cutaneous perforators from the radial and ulnar arteries in the forearm. This study aimed to map the location of the cutaneous perforators that arise directly from the radial and ulnar arteries in cadavers.

Methods: Twenty-nine human cadaveric forearms were dissected. All radial and ulnar arteries cutaneous perforators were analyzed for total number and distribution. To define the distribution of each cutaneous perforator, the forearm was divided into 10 sections, with the sections labeled as 10%, 20%, 30%, and so on, beginning at the wrist.

Results: From the radial artery, there were a total of 262 skin perforators with an average of 9.03 ± 2.28 (mean ± SD) per limb, whereas the total was 159 from the ulnar artery, with an average of 5.48 ± 1.49 per limb. Additionally, 128 (49%) radial artery cutaneous perforators and 75 (47%) from the ulnar artery were concentrated in the 0-30% section of the forearm. Both the radial and ulnar arteries had many cutaneous perforators in the forearm section labeled 70%, with 32 of 262 (12%) cutaneous perforators of the radial artery and 27 of 159 (17%) cutaneous perforators of the ulnar artery located here.

Conclusions: There were more cutaneous perforators from the radial artery than from the ulnar artery, and both were concentrated in the distal one-third of the forearm and in the forearm section labeled 70%. This information could be helpful when harvesting forearm flaps.
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http://dx.doi.org/10.1097/GOX.0000000000001550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682188PMC
October 2017

MafB enhances efferocytosis in RAW264.7 macrophages by regulating Axl expression.

Immunobiology 2018 01 6;223(1):94-100. Epub 2017 Oct 6.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.

The transcription factor MafB is involved in cellular differentiation and phagocytosis in macrophages. Macrophages phagocytose apoptotic cells in vivo; this process, which is known as efferocytosis, requires Axl receptor tyrosine kinase (Axl) activity. However, the association between MafB and efferocytosis, as well as that between MafB and Axl, in macrophages is unknown. We hypothesized that MafB modulates macrophage efferocytosis by regulating Axl expression. Fluorescent-labeled apoptotic thymocytes were added to RAW264.7-MafB-shRNA and control cells, and the proportion of phagocytosis-positivey fluorescence microscopy and flow cytometry. In addition, Axl mRNA and protein were quantified by real-time PCR and western blotting in each group. RAW264.7-MafB-shRNA cells were transfected with a plasmid expressing green fluorescent protein (GFP)-tagged Axl or a control empty plasmid expressing only GFP. The capacity for phagocytosis of apoptotic cells was assessed in GFP-positive cells gated based on fluorescence intensity. In RAW264.7-MafB-shRNA cells, capacity for phagocytosis of apoptotic thymocytes was significantly reduced compared with that of control cells, as determined by fluorescence microscope and flow cytometry. Axl mRNA and protein expression was significantly reduced in RAW264.7-MafB-shRNA cells relative to control cells. Furthermore, the capacity of RAW264.7-MafB-shRNA cells, transfected with an Axl-expressing plasmid, for phagocytosis of apoptotic thymocytes was significantly greater than that of cells transfected with the control plasmid. Collectively, the present findings indicate that MafB enhances efferocytosis by regulating Axl expression in RAW264.7 macrophages.
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http://dx.doi.org/10.1016/j.imbio.2017.10.007DOI Listing
January 2018

MafB silencing in macrophages does not influence the initiation and growth of lung cancer induced by urethane.

EXCLI J 2017 20;16:914-920. Epub 2017 Jun 20.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.

An increased number of tumor-associated macrophages (TAMs) that exhibit the M2 macrophage phenotype is related to poorer prognosis in cancer patients. MafB is a transcription factor regulating the differentiation of macrophages. However, involvement of MafB for the development of TAMs is unknown. This study was designed to investigate the role of MafB in a murine urethane-induced lung cancer model. Urethane was injected intraperitoneally into wild-type and dominant-negative MafB transgenic mice. Twenty-four weeks later, mice were sacrificed and their lungs removed for pathological analysis. The numbers and mean areas of lung cancer were evaluated. In addition, the numbers of Mac-3-positive macrophages were evaluated in each tumor. The numbers and mean areas of lung cancer induced by urethane administration were not significantly different between wild-type and dominant-negative MafB transgenic mice. The numbers of TAMs in lung cancer tissue were not significantly different between the two groups. MafB silencing using dominant-negative MafB did not influence the initiation and growth of lung cancer in mice exposed to urethane. These data suggest that MafB may not be related to the development of TAMs.
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http://dx.doi.org/10.17179/excli2017-325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579402PMC
June 2017
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