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1. Multi-biome analysis identifies distinct gut microbial signatures and their crosstalk in ulcerative colitis and Crohn’s disease

Author: Shintaro Akiyama, Suguru Nishijima, Yasushi Kojima, Moto Kimura, Mitsuru Ohsugi, Kohjiro Ueki, Masashi Mizokami, Masahira Hattori, Kiichiro Tsuchiya, Naomi Uemura, Takashi Kawai, Peer Bork, and Naoyoshi Nagata
Subjects: Science
Abstract: Abstract The integrative multi-kingdom interaction of the gut microbiome in ulcerative colitis (UC) and Crohn’s disease (CD) remains underinvestigated. Here, we perform shotgun metagenomic sequencing of feces from patients with UC and CD, and healthy controls in the Japanese 4D cohort, profiling bacterial taxa, gene functions, and antibacterial genes, bacteriophages, and fungi. External metagenomic datasets from the US, Spain, the Netherlands, and China were analyzed to validate our multi-biome findings. We found that Enterococcus faecium and Bifidobacterium spp. were enriched in both diseases. Enriched Escherichia coli was characteristic of CD and was linked to numerous antibiotic resistance genes involved in efflux pumps and adherent-invasive Escherichia coli virulence factors. Virome changes correlated with shifts in the bacteriome, including increased abundances of phages encoding pathogenic genes. Saccharomyces paradoxus and Saccharomyces cerevisiae were enriched in UC and CD, respectively. Saccharomyces cerevisiae and Escherichia coli had negative associations with short-chain fatty acid (SCFA)-producing bacteria in CD. Multi-biome signatures and their interactions in UC and CD showed high similarities between Japan and other countries. Since bacteria, phages, and fungi formed multiple hubs of intra- or trans-kingdom networks with SCFA producers and pathobionts in UC and CD, an approach targeting the interaction network may hold therapeutic promise.
Published: 2024
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2. Assessment of cancer risk associated with 7‐nitroso‐3‐(trifluoromethyl)‐5,6,7,8‐tetrahydro[1,2,4] triazolo‐[4,3‐a]pyrazine‐contaminated sitagliptin use: A retrospective cohort study

Author: Takehiro Sugiyama, Takashi Furuno, Yuichi Ichinose, Masao Iwagami, Noriko Ihana‐Sugiyama, Kenjiro Imai, Tamaki Kakuwa, Ryoko Rikitake, Mitsuru Ohsugi, Takahiro Higashi, Hiroyasu Iso, and Kohjiro Ueki
Subjects: Nitrosamines, Pharmacoepidemiology, Sitagliptin phosphate, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ABSTRACT Aims/Introduction A recent US Food and Drug Administration report highlighted concerns over nitrosamine (7‐nitroso‐3‐(trifluoromethyl)‐5,6,7,8‐tetrahydro[1,2,4] triazolo‐[4,3‐a]pyrazine [NTTP]) impurities in sitagliptin, prompting investigations into its safety profile. The present study aimed to determine if the use of NTTP‐contaminated sitagliptin, in comparison with other dipeptidyl peptidase‐4 (DPP‐4) inhibitors, is associated with an increased cancer risk. Materials and Methods This retrospective cohort study secondarily used the National Database of Health Insurance Claims and Specific Health Checkups of Japan, encompassing data on >120 million individuals. The study involved patients who initiated DPP‐4 inhibitor therapy (sitagliptin or other DPP‐4 inhibitors) and continued its exclusive use for 3 years. Sitagliptin users were compared with other DPP‐4 inhibitor users for assessing the occurrence of cancers, as defined by diagnosis codes. Further analyses focused on specific types of cancer, using either diagnosis codes or a combination of diagnosis and procedure codes. We also carried out various sensitivity analyses, including those with different exposure periods. Results Sitagliptin users (149,120 patients, 388,356 person‐years) experienced 9,643 cancer incidences (2,483.0/100,000 person‐years) versus 12,621 incidences (2,504.4/100,000 person‐years) among other DPP‐4 inhibitor users (199,860 patients, 503,952 person‐years), yielding a minimal difference (incidence rate ratio 0.99, 95% confidence interval 0.97–1.02). A multiple Cox proportional hazards model showed no significant association between sitagliptin use and overall cancer incidence (hazard ratio 1.01, 95% confidence interval 0.98–1.04). Findings were also consistent across cancer types and sensitivity analyses. Conclusions We observed no evidence to suggest an increased cancer risk among patients prescribed NTTP‐contaminated sitagliptin, although continued investigation is needed.
Published: 2024
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3. Association of biomarkers and Barthel Index with occurrence of age‐related adverse health outcomes in individuals with diabetes

Author: Kotaro Umamoto, Ryotaro Bouchi, Kotaro Soeda, Shosuke Satake, Tohru Hosoyama, Mitsuru Ohsugi, Kohjiro Ueki, and Hiroshi Kajio
Subjects: Aging, Biomarker, Diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction The clinical significance of age‐related biomarkers in patients with diabetes has not been fully elucidated. In this study, we aimed to establish models to predict the progression of aging in patients with diabetes using biomarkers. Materials and Methods This single‐center, retrospective cohort study included 115 Japanese patients with diabetes aged ≥60 years. Age‐related adverse health outcomes were defined as emergency hospitalization, any increase in the level of nursing care certification, admission to a nursing home or death. The associations of age‐related biomarker levels (adiponectin, growth differentiation factor 15 [GDF15], C‐X‐C motif chemokine ligand 9 and apelin) and clinical indicators with age‐related adverse health outcomes were evaluated. Factors that predominantly influenced the occurrence of age‐related adverse health outcomes were explored using the Cox proportional hazards model. Results The mean age of the 115 participants was 73 years, 50.6% were men, the mean body mass index and hemoglobin A1c level were 25.3 kg/m2 and 9.79%, respectively. There were 26 age‐related adverse health outcomes during the study period (median 1.93, range 0–4.65 years). In a model combining clinical indicators and biomarkers, including the Barthel Index, GDF15 and adiponectin, the occurrence of age‐related adverse health outcomes was found to be significantly associated with GDF15 and Barthel Index. The group with both GDF15 and adiponectin levels higher than the median proved to be significantly higher than the group with both lower. Conclusions The measurement of GDF15 and adiponectin levels and the Barthel Index might be useful for predicting age‐related adverse health outcomes in patients with diabetes.
Published: 2024
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4. Associations between income/employment status and diabetes care processes, health behaviors, and health outcomes in Japan: A cross‐sectional study using claims data linked to a questionnaire survey

Author: Takuya Yamaoka, Takehiro Sugiyama, Noriko Ihana‐Sugiyama, Akiko Kimura, Kouko Yamamoto, Kenjiro Imai, Naoaki Kuroda, Mitsuru Ohsugi, Kohjiro Ueki, Toshimasa Yamauchi, and Nanako Tamiya
Subjects: Claims analysis, Healthcare quality assessment, Socioeconomic status, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ABSTRACT Aims/Introduction We aimed to explore the associations between income/employment status and diabetes care processes, health behaviors and health outcomes. Materials and Methods This cross‐sectional study used health insurance claims data between April 2021 and March 2022, and a questionnaire survey between December 2022 and January 2023 in Tsukuba City. The study analyzed the participants with diabetes (other than type 1) from those selected by stratified random sampling. We evaluated diabetes care processes, health behaviors and health outcomes by calculating weighted proportions among the groups. We also assessed the associations between income/employment status and these variables using multivariable modified Poisson regression models. Results Of the 264 identified participants, 161 (64.2%) were men and 168 (72.8%) were aged ≥65 years old. Compared with the low‐income groups, the high‐income group had a higher proportion of sodium–glucose cotransporter 2 inhibitors or glucagon‐like peptide‐1 receptor agonists use (adjusted risk ratio [aRR] 1.70, 95% confidence interval (CI) 1.07–2.72), a higher proportion of attendance to annual health checkups for ≥2 years (aRR 1.68, 95% CI 1.07–2.64) and a lower proportion of all‐cause hospitalization (aRR 0.15, 95% CI 0.04–0.48); additionally, the middle‐income group had a lower proportion of high total outpatient medical expenses (aRR 0.57, 95% CI 0.35–0.92). Compared to the no work time group, the full‐time work group had a lower proportion of exercise habits (aRR 0.59, 95% CI 0.35–0.99) and a higher proportion of good self‐reported health (aRR 2.08, 95% CI 1.22–3.55). Conclusions Several variables were associated with income/employment status. Policy intervention should focus on high‐risk groups identified by considering these associations.
Published: 2024
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5. Implementation rate of diabetic self‐management education and support for Japanese people with diabetes using the National Database

Author: Noriko Ihana‐Sugiyama, Takehiro Sugiyama, Kenjiro Imai, Mitsuru Ohsugi, Kohjiro Ueki, Toshimasa Yamauchi, and Takashi Kadowaki
Subjects: Claims data, Diabetic education, Self‐management, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract People with diabetes are encouraged to receive diabetes self‐management education and support (DSMES) appropriately. However, in Japan, the implementation rates of DSMES are not known. DSMES implementation rates were calculated using the National Database of claims data, which included nearly all insurance‐covered medical procedures. The study enrolled participants who received regular antidiabetic medications between April 2017 and March 2018. The implementation rates of DSMES‐related care were calculated by characteristics, visiting medical facilities and prefectures. In 4,465,513 participants receiving antidiabetic medications (men, 57.8%; insulin use, 14.1%), nutrition guidance (5.6%) was the most frequently provided care type. Insulin users and participants visiting Japan Diabetes Society‐certified and large medical institutions had higher implementation rates of nutrition guidance. DSMES‐related care might not be provided adequately for Japanese people with diabetes. Further studies are needed to develop an optimal diabetes care system.
Published: 2024
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6. A case of type 2 diabetes mellitus with weight gain and worsening of glycemic management after tezepelumab administration for severe bronchial asthma

Author: Kotaro Umamoto, Ryotaro Bouchi, Noriko Ihana‐Sugiyama, Noriko Kodani, Mitsuru Ohsugi, Masayuki Hojo, Kohjiro Ueki, and Hiroshi Kajio
Subjects: Asthma, Obesity, Tezepelumab, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Some cases of bronchial asthma are refractory to conventional therapies. As the pathogenesis of bronchial asthma has been clarified, new treatments, such as bronchial thermoplasty and biological drugs, have been developed. Tezepelumab, an anti‐thymic stromal lymphopoietin antibody, has been reported to inhibit the exacerbation of severe asthma; however, its adverse effects on glucose metabolism have not yet been reported. We encountered a case of weight gain and worsening glycemic management in a patient with type 2 diabetes and refractory bronchial asthma after the initiation of tezepelumab treatment. It has been reported that the overexpression of thymic stromal lymphopoietin in mice resulted in an enhanced release of free fatty acids from adipose tissues and the liver; thus, the administration of anti‐thymic stromal lymphopoietin antibodies in the present case might have caused obesity, fatty liver and lower glucose tolerance.
Published: 2024
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7. Impact of COVID‐19 pandemic on behavioral changes and glycemic control and a survey of telemedicine in patients with diabetes: A multicenter retrospective observational study

Author: Ryotaro Bouchi, Takehiro Sugiyama, Atsushi Goto, Mitsuru Ohsugi, Narihito Yoshioka, Hideki Katagiri, Tomoya Mita, Yushi Hirota, Hiroshi Ikegami, Munehide Matsuhisa, Eiichi Araki, Hiroki Yokoyama, Masae Minami, Katsuya Yamazaki, Hideaki Jinnouchi, Hiroki Ikeda, Hitomi Fujii, Miyuki Nogawa, Masahiro Kaneshige, Kengo Miyo, and Kohjiro Ueki
Subjects: COVID‐19, glycemic control, lifestyle changes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ABSTRACT Aims/Introduction To investigate whether the COVID‐19 pandemic affected behavioral changes and glycemic control in patients with diabetes and to conduct a survey of telemedicine during the pandemic. Materials and Methods In this retrospective study, a total of 2,348 patients were included from 15 medical facilities. Patients were surveyed about their lifestyle changes and attitudes toward telemedicine. Hemoglobin A1c (HbA1c) levels were compared among before (from June 1 to August 31, 2019) and in the first (from June 1 to August 31, 2020) and in the second (from June 1 to August 31, 2021) year of the pandemic. A survey of physician attitudes toward telemedicine was also conducted. Results The HbA1c levels were comparable between 2019 (7.27 ± 0.97%), 2020 (7.28 ± 0.92%), and 2021 (7.25 ± 0.94%) without statistical difference between each of those 3 years. Prescriptions for diabetes medications increased during the period. The frequency of eating out was drastically reduced (51.7% in 2019; 30.1% in 2020), and physical activity decreased during the pandemic (48.1% in 2019; 41.4% in 2020; 43.3% in 2021). Both patients and physicians cited increased convenience and reduced risk of infection as their expectations for telemedicine, while the lack of physician–patient interaction and the impossibility of consultation and examination were cited as sources of concern. Conclusions Our data suggest that glycemic control did not deteriorate during the COVID‐19 pandemic with appropriate intensification of diabetes treatment in patients with diabetes who continued to attend specialized diabetes care facilities, and that patients and physicians shared the same expectations and concerns about telemedicine.
Published: 2023
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8. Patient referral flow between physician and ophthalmologist visits for diabetic retinopathy screening among Japanese patients with diabetes: A retrospective cross‐sectional cohort study using the National Database

Author: Noriko Ihana‐Sugiyama, Takehiro Sugiyama, Takao Hirano, Kenjiro Imai, Mitsuru Ohsugi, Ryo Kawasaki, Toshinori Murata, Youichiro Ogura, Kohjirou Ueki, Toshimasa Yamauchi, and Takashi Kadowaki
Subjects: Claims analysis, Diabetic retinopathy, Healthcare quality assessment, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Regular screening for diabetic retinopathy is essential. This study aimed to show the process and current situation of diabetic retinopathy screening prescribed by physicians (internists) and ophthalmologists for Japanese patients with diabetes. Materials and Methods This retrospective cohort study used data from the Japanese National Database of Insurance Claims between April 2016 and March 2018. Ophthalmology visits and fundus examinations are defined using specific medical procedure codes. The proportion of ophthalmology visits for patients with diabetic medication and for fundus examination among those who visited ophthalmologists was calculated in the fiscal year 2017. A modified Poisson regression analysis was carried out to identify factors associated with retinopathy screening. Similarly, quality indicators by prefectures were also calculated. Results Among 4,408,585 patients receiving diabetic medications (57.8% men, 14.1% insulin use), 47.4% visited the ophthalmology department and 96.9% of those underwent fundus examination. Regression analysis showed that female sex, older age, insulin use, medical facilities with Japan Diabetes Society certification and large medical facilities were predictors of fundus examination. By prefecture, the ophthalmology consultation rate and the fundus examination ranged 38.5–51.0% and 92.1–98.7%, respectively. Conclusions Less than half of the patients who were prescribed antidiabetic medication by their physicians visited an ophthalmologist. However, most of the patients who visited an ophthalmologist had a fundus examination carried out. A similar tendency was noted for each prefecture. It is essential to reaffirm the necessity of recommending ophthalmologic examinations to physicians and healthcare professionals who care for patients with diabetes.
Published: 2023
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9. A single-center retrospective study on the clinical features of thyrotoxic periodic paralysis.

Author: Kota Yamada, Akiyo Tanabe, Makiko Hashimoto, Mitsuru Ohsugi, Kohjiro Ueki, and Hiroshi Kajio
Subjects: Medicine, Science
Abstract: PurposeThyrotoxic periodic paralysis (TPP) is characterized by muscle paralysis and significant intracellular potassium movement resulting in hypokalemia. Since TPP is a rare condition, only a few studies have explicated the clinical characteristics of patients with this disease. This study aimed to elucidate the clinical characteristics of patients with TPP by comparing them with those with thyrotoxicosis without paralysis (non-TPP) and sporadic periodic paralysis (SPP).MethodsThis was a single-center retrospective cohort study. Clinical data of patients with hyperthyroidism (n = 62) or periodic paralysis (n = 92) who were emergently admitted to our hospital was extracted from the electronic medical records and analyzed.ResultsAll patients in the TPP group (15 males and 2 females) had Graves' disease, with 14 being newly diagnosed. The average serum potassium level on admission was 2.3±0.75 mEq/L. No significant correlation was observed among serum potassium level, amount of potassium required for normalization, and thyroid hormone levels. The TPP group showed significantly younger age, higher male ratio and body mass index (BMI), and lower serum potassium and phosphorus levels than the non-TPP group, which comprised 36 patients with Graves' disease. No significant differences were observed between the TPP and SPP (n = 11) groups in terms of age, sex, BMI, serum electrolyte levels, potassium requirement for normalization, and recovery time.Main conclusionsConsidering that most patients with TPP have undiagnosed Graves' disease, distinguishing TPP from SPP based on clinical information and course alone is difficult in emergency settings. Therefore, for early detection and launch of specific treatment of Graves' disease, screening for thyroid hormone and anti-thyroid stimulating hormone receptor antibody levels is necessary when treating patients with periodic paralysis.
Published: 2024
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10. Different incidences of diabetic retinopathy requiring treatment since diagnosis according to the course of diabetes diagnosis: a retrospective cohort study

Author: Takehiro Sugiyama, Ayako Yanagisawa-Sugita, Hirokazu Tanaka, Noriko Ihana-Sugiyama, Kenjiro Imai, Mitsuru Ohsugi, Kohjiro Ueki, Nanako Tamiya, and Yasuki Kobayashi
Subjects: Medicine, Science
Abstract: Abstract We aimed to estimate the cumulative incidence of treatment-requiring diabetic retinopathy since clinical diagnosis of diabetes based on the course of diagnosis in a retrospective cohort study using Japan’s medical claims and health checkup data (JMDC Claims Database; 2009–2020). We included patients whose diabetes was first diagnosed at medical facilities (hospitals/clinics). We grouped them by health checkup participation before diagnosis, health checkup results, and antidiabetic medication promptly after the diagnosis. The incidence of treatment-requiring diabetic retinopathy (laser photocoagulation, intraocular injection, or vitrectomy) was compared among the groups. Of 126,696 patients, those who started an antidiabetic medication promptly after diabetes diagnosis without a recent health checkup faced the highest risk of treatment-requiring diabetic retinopathy (1-/5-year cumulative incidence: 3.1%/6.0%). This increased risk was consistently observed across various analyses, including the Cox proportional hazard model, sensitivity analysis restricting to those with an eye examination, and sensitivity analysis using vitrectomy as the outcome. Among patients with HbA1c ≥ 6.5% at recent health checkups, those who promptly started an antidiabetic medication had a higher risk (1.4%/3.8%) than those who did not (0.7%/2.7%). Taking the information about the course of diabetes diagnosis is important to manage risk stratification for diabetic retinopathy appropriately.
Published: 2023
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11. Proportion of subsequent clinic visits among persons without regular clinic visits who were screened as having hyperglycemia: A retrospective cohort study

Author: Hiroshi Matsumura, Takahiro Sugiyama, Nobuo Sakata, Noriko Ihana‐Sugiyama, Kenjiro Imai, Mitsuru Ohsugi, Kohjiro Ueki, Nanako Tamiya, and Hiroyasu Iso
Subjects: Diabetes mellitus, Diagnostic screening programs, Office visits, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction We aimed to examine the proportion of subsequent clinic visits for persons screened as having hyperglycemia based on glycated hemoglobin (HbA1c) levels at screening and the presence/absence of hyperglycemia at health checkups before 1 year of the screening among those without previous diabetes‐related medical care and attending regular clinic visits. Materials and methods This retrospective cohort study used the 2016–2020 data of Japanese health checkups and claims. The study analyzed 8,834 adult beneficiaries aged 20–59 years without regular clinic visits who had never received diabetes‐related medical care and whose recent health checkups showed hyperglycemia. The rates of 6‐month subsequent clinic visits after health checkups were evaluated according to HbA1c levels and the presence/absence of hyperglycemia at checkups a year before. Results The overall clinic visit rate was 21.0%. The HbA1c‐specific rates were 17.0, 26.7, 25.4 and 28.4% for
Published: 2023
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12. Association of acute‐to‐chronic glycemic ratio and outcomes in patients with COVID‐19 and undiagnosed diabetes mellitus: A retrospective nationwide cohort study

Author: Masaki Uchihara, Takehiro Sugiyama, Ryotaro Bouchi, Nobuaki Matsunaga, Yusuke Asai, Hiroyuki Gatanaga, Mitsuru Ohsugi, Norio Ohmagari, Hiroshi Kajio, and Kohjiro Ueki
Subjects: Acute‐to‐chronic glycemic ratio, COVID‐19, Undiagnosed diabetes mellitus, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction To assess the association of undiagnosed diabetes mellitus and its acute‐to‐chronic glycemic ratio with clinical outcome in patients hospitalized with coronavirus disease 2019 (COVID‐19) using a large‐scale nationwide registry in Japan. Materials and Methods Overall, 4,747 patients were included between July 2021 and January 2022. We evaluated blood glucose and glycated hemoglobin levels at admission, and calculated the acute‐to‐chronic glycemic ratio for each non‐diabetes mellitus, undiagnosed diabetes mellitus and pre‐existing diabetes mellitus group. The primary composite outcome comprised in‐hospital mortality, invasive mechanical ventilation, extracorporeal membrane oxygenation support, intensive care unit admission and transfer to a more advanced medical facility. Results Compared with the non‐diabetes mellitus group, the undiagnosed diabetes mellitus group was significantly associated with a worse COVID‐19 outcome (odds ratio 2.18, 95% confidence interval 1.50–3.18). In patients with undiagnosed diabetes mellitus, the 3rd tertile of the acute‐to‐chronic glycemic ratio was linked with a worse COVID‐19 outcome compared with the 1st tertile (odds ratio 3.33, 95% confidence interval 1.43–7.77), whereas glycated hemoglobin levels were not; among patients with pre‐existing diabetes mellitus, glycated hemoglobin levels were linked with a worse outcome. Conclusions Among patients with undiagnosed diabetes mellitus with COVID‐19, the magnitude of elevation of blood glucose from chronic to acute levels is associated with worse outcomes.
Published: 2023
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13. New‐onset type 1 diabetes and Graves' disease after antiretroviral therapy in a patient with human immunodeficiency virus infection

Author: Maho Taguchi, Noriko Ihana‐Sugiyama, Daisuke Shiojiri, Kazuo Izumi, Michi Kobayashi, Noriko Kodani, Ryotaro Bouchi, Mitsuru Ohsugi, Akiyo Tanabe, Kohjiro Ueki, and Hiroshi Kajio
Subjects: Antiretroviral therapy, Immune‐inflammatory reconstitution syndrome, Type 1 diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Patients with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy can develop autoimmune diseases, referred to as immune‐inflammatory reconstitution syndrome. Nevertheless, only a few reports on the onset of type 1 diabetes as immune‐inflammatory reconstitution syndrome are available. A 40‐year‐old Japanese man with HIV infection was initiated with antiretroviral therapy at the age of 29 years. He developed Graves' disease at 35 years and diabetes, with a hemoglobin A1c of 6.5%, and maintained insulin secretion at 38 years. His antiglutamic acid decarboxylase antibody level was >2,000 U/mL, and he was diagnosed with slowly progressive type 1 diabetes. At the age of 40 years, he was admitted to our hospital with diabetic ketosis. We retrospectively assayed his stored plasma samples for thyroid‐stimulating hormone receptor antibody and antiglutamic acid decarboxylase antibody, which showed positive conversion after initiating antiretroviral therapy, suggesting that Graves' disease and type 1 diabetes developed as a probable result of immune‐inflammatory reconstitution syndrome.
Published: 2023
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14. False-positive 123I-metaiodobenzylguanidine scintigraphy in a patient with a gastrointestinal stromal tumor presenting as a left adrenal incidentaloma

Author: Erika Sugito, Akiyo Tanabe, Koji Maruyama, Kyoko Nohara, Naoki Enomoto, Ryotaro Bouchi, Mitsuru Ohsugi, Kohjiro Ueki, Kazuhiko Yamada, and Hiroshi Kajio
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: A 47-year-old man was diagnosed with a left adrenal incidentaloma at 40 years of age. The tumor had irregular margins and grew from 18 mm to 30 mm in maximum diameter over 7 years. On computed tomography scan, the mass appeared to localize within the tip of the lateral limb of the left adrenal gland, and between the left adrenal gland and the posterior wall of the stomach. The plasma corticotropin and cortisol concentrations and the 24-h urine fractionated metanephrine levels were normal. 123I-metaiodobenzylguanidine scintigraphy showed tumor avidity consistent with a hormonally inactive pheochromocytoma. A laparoscopic left adrenalectomy was performed; however, no tumor was present in the resected specimen. Abdominal computed tomography postoperatively showed that the tumor remained intact and appeared to connect to the posterior wall of the stomach. A laparotomy was performed and the tumor was removed. The tumor was localized to the intraperitoneal space and isolated from the posterior wall of the stomach. The pathological diagnosis was a gastrointestinal stromal tumor. Clinicians need to be aware of the limitations of diagnostic imaging studies in diagnosing non-functioning adrenal incidentalomas, which require a pathological analysis for the final diagnosis. Moreover, clinicians need to provide patients with sufficient informed consent when deciding on treatment strategies.
Published: 2023
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15. Influence of the COVID-19 Pandemic on Overall Physician Visits and Telemedicine Use Among Patients With Type 1 or Type 2 Diabetes in Japan

Author: Susumu Yagome, Takehiro Sugiyama, Kosuke Inoue, Ataru Igarashi, Ryotaro Bouchi, Mitsuru Ohsugi, Kohjiro Ueki, and Atsushi Goto
Subjects: covid-19, telemedicine, outpatient, diabetes, Medicine (General), R5-920
Abstract: Background: Regular visits with healthcare professionals are important for preventing serious complications in patients with diabetes. The purpose of this retrospective cohort study was to clarify whether there was any suppression of physician visits among patients with diabetes during the spread of the novel coronavirus 2019 (COVID-19) in Japan and to assess whether telemedicine contributed to continued visits. Methods: We used the JMDC Claims database, which contains the monthly claims reported from July 2018 to May 2020 and included 4,595 (type 1) and 123,686 (type 2) patients with diabetes. Using a difference-in-differences analysis, we estimated the changes in the monthly numbers of physician visits or telemedicine per 100 patients in April and May 2020 compared with the same months in 2019. Results: For patients with type 1 diabetes, the estimates for total overall physician visits were −2.53 (95% confidence interval [CI], −4.63 to 0.44) in April and −8.80 (95% CI, −10.85 to −6.74) in May; those for telemedicine visits were 0.71 (95% CI, 0.47–0.96) in April and 0.54 (95% CI, 0.32–0.76) in May. For patients with type 2 diabetes, the estimates for overall physician visits were −2.50 (95% CI, −2.95 to −2.04) in April and −3.74 (95% CI, −4.16 to −3.32) in May; those for telemedicine visits were 1.13 (95% CI, 1.07–1.20) in April and 0.73 (95% CI, 0.68–0.78) in May. Conclusion: The COVID-19 pandemic was associated with suppression of physician visits and a slight increase in the utilization of telemedicine among patients with diabetes during April and May 2020.
Published: 2022
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16. Extensive gut virome variation and its associations with host and environmental factors in a population-level cohort

Author: Suguru Nishijima, Naoyoshi Nagata, Yuya Kiguchi, Yasushi Kojima, Tohru Miyoshi-Akiyama, Moto Kimura, Mitsuru Ohsugi, Kohjiro Ueki, Shinichi Oka, Masashi Mizokami, Takao Itoi, Takashi Kawai, Naomi Uemura, and Masahira Hattori
Subjects: Science
Abstract: Here, Nishijima et al. perform a large-scale analysis of the human gut virome in the Japanese 4D cohort of 4198 deeply phenotyped individuals, revealing thousands of bacteriophage genomes, virus-bacteria interactions, and describing associations with various host and environmental factors.
Published: 2022
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17. Impact of newly diagnosed diabetes on coronavirus disease 2019 severity and hyperglycemia

Author: Masaki Uchihara, Ryotaro Bouchi, Noriko Kodani, Sho Saito, Yusuke Miyazato, Kotaro Umamoto, Hirofumi Sugimoto, Michi Kobayashi, Sayaka Hikida, Yutaro Akiyama, Noriko Ihana‐Sugiyama, Mitsuru Ohsugi, Akiyo Tanabe, Kohjiro Ueki, Jin Takasaki, Masayuki Hojo, and Hiroshi Kajio
Subjects: COVID‐19, Diabetes, Hyperglycemia, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ABSTRACT Aims/Introduction Diabetes is associated with poor clinical outcomes of coronavirus disease 2019 (COVID‐19). However, the impact of newly diagnosed diabetes on prognosis has not been clarified. The objective of this study was to show the features and outcome of COVID‐19 patients with newly diagnosed diabetes in Japan. Materials and Methods We retrospectively analyzed 62 patients with diabetes hospitalized for COVID‐19 between 1 April and 18 August 2021 at the National Center for Global Health and Medicine in Tokyo, Japan. We evaluated the worst severity of COVID‐19 and plasma blood glucose levels in patients with newly diagnosed diabetes or pre‐existing diabetes. Results This study included 62 confirmed COVID‐19 patients with diabetes, including 19 (30.6%) patients with newly diagnosed diabetes and 43 (69.4%) patients with pre‐existing diabetes. Patients with newly diagnosed diabetes significantly progressed to a critical condition more frequently during hospitalization than patients with pre‐existing diabetes (52.6% vs 20.9%, P = 0.018). In addition, patients with newly diagnosed diabetes had significantly higher average plasma blood glucose levels for the first 3 days after admission than those with pre‐existing diabetes. Conclusions Our study suggests that the proportion of COVID‐19 patients who are newly diagnosed with diabetes is high, and they have an increased risk of developing severe disease than those with pre‐existing diabetes. It might be advisable that at the point of COVID‐19 diagnosis, blood glucose and glycated hemoglobin levels be assessed in all patients.
Published: 2022
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18. Living and working environments are important determinants of glycemic control in patients with diabetes during the COVID‐19 pandemic: A retrospective observational study

Author: Aiko Terakawa, Ryotaro Bouchi, Noriko Kodani, Tomoko Hisatake, Takehiro Sugiyama, Michihiro Matsumoto, Noriko Ihana‐Sugiyama, Mitsuru Ohsugi, Kohjiro Ueki, and Hiroshi Kajio
Subjects: COVID‐19, Glycemic control, Lifestyle changes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aim To investigate (1) the association of lifestyle changes and living and working conditions with glycemic control and (2) whether treatment was intensified appropriately in patients with diabetes under the first COVID‐19 state of emergency in Japan. Materials and Methods A total of 321 participants were included. Participants completed a questionnaire regarding lifestyle changes, including diet, physical activity, and living and working conditions during the COVID‐19 pandemic. The change in hemoglobin A1c (HbA1c) levels was estimated before (June 1, 2019 to August 31, 2019) and during (June 1, 2020 to August 31, 2020) the pandemic. Factors associated with changes in HbA1c levels were examined by multiple linear regression analysis. The proportion of patients who received treatment intensification for diabetes was compared between before and during the pandemic. Results There was no significant change in HbA1c levels before the pandemic and during the pandemic (7.13 ± 0.98% vs 7.18 ± 1.01%, P = 0.186). Teleworking (estimate 0.206, P = 0.004) and living with a dog (estimate −0.149, P = 0.038) were significantly associated with changes in HbA1c levels after adjusting for covariates. There was no significant difference in the proportion of patients who received treatment intensification for diabetes during the pandemic and before the pandemic in either the elderly or non‐elderly patients. Conclusions Overall glycemic control did not worsen during the pandemic. Nonetheless, environmental factors, including telework, were found to influence glycemic control in patients with diabetes. Further studies are needed to clarify whether the COVID‐19 pandemic could affect treatment intensification for diabetes.
Published: 2022
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19. Factors associated with the degree of glycemic deterioration among patients with type 2 diabetes who dropped out of diabetes care: A longitudinal analysis using medical claims and health checkup data in Japan

Author: Noriko Ihana‐Sugiyama, Takehiro Sugiyama, Kenjiro Imai, Ayako Yanagisawa‐Sugita, Hirokazu Tanaka, Mitsuru Ohsugi, Kohjiro Ueki, Nanako Tamiya, and Yasuki Kobayashi
Subjects: Type 2 diabetes, Dropout, Glycemic control, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ABSTRACT Aims/Introduction To identify factors associated with worsening glycemic control after discontinuing diabetes care among patients with type 2 diabetes. Materials and Methods This retrospective cohort study combined medical claims and health checkup data between January 2005 and April 2018. Adult Japanese workers with type 2 diabetes who had dropped out from diabetes care for ≥4 months after receiving ≥18 months of non‐intermittent care and had health checkup information both before and after the dropout were included. Factors associated with changes in HbA1c during the dropout period were identified using multiple linear regression analyses and depicting restricted cubic spline (RCS) curves. Results A total of 1,125 patients (mean age: 51.2 years, baseline HbA1c: 6.8%, and number of males: 93.7%) whose follow‐up HbA1c increased to 7.6% after a mean 9.3‐month dropout period were included. Deterioration in HbA1c was associated with higher baseline HbA1c and sulfonylurea or insulin use. The RCS curves illustrated that patients without antidiabetic medication had small changes in HbA1c (+0.5% from a baseline HbA1c of 7.0%), whereas those using sulfonylureas or insulin had an approximately 2% or more increase in HbA1c even when maintaining reasonable glycemic control before dropping out. Conclusions Overall in this study, glycemic control worsened during treatment interruptions among patients who were mainly male employees. However, changes in HbA1c greatly varied based on baseline HbA1c and antidiabetic medication type. Caring for patients at risk of worsening glycemic control due to treatment dropout, especially those using sulfonylurea and insulin, is imperative.
Published: 2022
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20. Retrospective nationwide study on the trends in first‐line antidiabetic medication for patients with type 2 diabetes in Japan

Author: Ryotaro Bouchi, Takehiro Sugiyama, Atsushi Goto, Kenjiro Imai, Noriko Ihana‐Sugiyama, Mitsuru Ohsugi, Toshimasa Yamauchi, Takashi Kadowaki, and Kohjiro Ueki
Subjects: Antidiabetic agents, First‐line therapy, Type 2 diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction To investigate the national trend in the prescription of first‐line non‐insulin antidiabetic agents and total medical costs (TMCs) after prescribing the drug in Japanese patients with type 2 diabetes. Materials and Methods Using the National Database of Health Insurance Claims and Specific Health Check‐ups of Japan covering almost the entire Japanese population, we calculated the proportion of each antidiabetic drug from 2014 to 2017, and determined the factors associated with drug selection. The TMCs in the first year after starting the drugs were calculated, and factors associated with the costs were also determined. Results Among 1,136,723 new users of antidiabetic agents, dipeptidyl peptidase‐4 inhibitors were the most prescribed (65.1%), followed by biguanides (15.9%) and sodium–glucose cotransporter 2 inhibitors (7.6%). Sodium–glucose cotransporter 2 inhibitor and biguanide use increased during 2014–2017 (2.2%–11.4% and 13.7%–17.2%, respectively), whereas the others decreased. Biguanides were not prescribed at all in 38.2% of non‐Japan Diabetes Society‐certified facilities. The TMCs were the lowest among those who started with biguanides. Fiscal year, age, sex, facility, number of beds and comorbidities were associated with drug choice and TMCs. There were wide regional variations in the drug choice, but not in the TMCs. Conclusions Unlike in the USA and Europe, dipeptidyl peptidase‐4 inhibitor is the most prescribed first‐line medication for type 2 diabetes patients in Japan, while there is a wide variation in the drug choice by facility‐type and prefecture.
Published: 2022
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21. Evaluation of cellular and humoral autoimmunity before the development of type 1 diabetes in a patient with idiopathic CD4 lymphocytopenia

Author: Koji Maruyama, Daisuke Chujo, Koji Watanabe, Akitsu Kawabe, Takehiro Sugiyama, Mitsuru Ohsugi, Akiyo Tanabe, Kohjiro Ueki, and Hiroshi Kajio
Subjects: Idiopathic CD4 lymphocytopenia, T cells, Type 1 diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract A 64‐year‐old woman developed type 1 diabetes 23 years after the diagnosis of idiopathic CD4 lymphocytopenia. To investigate the etiological interaction between idiopathic CD4 lymphocytopenia and type 1 diabetes, we carried out a longitudinal analysis related to islet‐specific autoimmunity. Anti‐glutamic acid decarboxylase antibody had been already weakly positive for at least 16 years and started rising at 6 months before the onset of type 1 diabetes. The seroconversion of anti‐insulinoma‐associated antigen‐2 antibody and insulin autoantibody occurred at the time of onset. The ratio of CD8/CD4 had been gradually increasing for 8 years before type 1 diabetes onset. Notably, islet‐specific glucose‐6‐phosphatase catalytic subunit‐related protein‐reactive CD8+ T cells were detected at type 1 diabetes onset, and the frequency was higher than that in 15 non‐diabetic controls (6.75% vs 0.49 ± 0.78%, mean ± SD). The present type 1 diabetes patient, presented with idiopathic CD4 lymphocytopenia and showed an elevated number of CD8+ T cells, including the islet antigen‐specific CD8+ T cells that might contribute to autoimmune destruction of pancreatic β‐cells.
Published: 2019
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22. Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism

Author: Takayoshi Sasako, Mitsuru Ohsugi, Naoto Kubota, Shinsuke Itoh, Yukiko Okazaki, Ai Terai, Tetsuya Kubota, Satoshi Yamashita, Kunio Nakatsukasa, Takumi Kamura, Kaito Iwayama, Kumpei Tokuyama, Hiroshi Kiyonari, Yasuhide Furuta, Junji Shibahara, Masashi Fukayama, Kenichiro Enooku, Kazuya Okushin, Takeya Tsutsumi, Ryosuke Tateishi, Kazuyuki Tobe, Hiroshi Asahara, Kazuhiko Koike, Takashi Kadowaki, and Kohjiro Ueki
Subjects: Science
Abstract: Endoplasmic reticulum (ER) stress has been proposed to play a role in metabolic diseases. Here, Sasako and colleagues identify stromal cell-derived factor 2 like 1 (Sdf2l1) as a regulator of the ER stress response to feeding in the liver, and suggest that its downregulation may promote diabetes and hepatic steatosis in humans.
Published: 2019
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23. Contribution of Diabetes to the Incidence and Prevalence of Comorbid Conditions (Cancer, Periodontal Disease, Fracture, Impaired Cognitive Function, and Depression): A Systematic Review of Epidemiological Studies in Japanese Populations

Author: Hirokazu Tanaka, Noriko Ihana-Sugiyama, Takehiro Sugiyama, and Mitsuru Ohsugi
Subjects: diabetes mellitus, diabetes complications, epidemiological studies, review, Japan, Medicine (General), R5-920
Abstract: Background: Several epidemiological studies have determined the relationship between diabetes and the incidence and/or prevalence of recently identified comorbid conditions (cancer, periodontal disease, fracture, cognitive impairment, and depression). These relationships may vary by country or race/ethnicity. We aimed to systematically review studies in this field conducted with the Japanese population because such a review in the Japanese population has never been undertaken. Methods: We conducted systematic literature searches in PubMed and Ichushi-Web databases for studies published until December 2016. Studies comparing the incidence and/or prevalence of the comorbidities among the Japanese population were included. The studies were classified as integrated analyses, cohort studies, case-control studies, or cross-sectional studies. Results: We identified 33 studies (cancer: 17, periodontal disease: 5, fracture: 5, cognitive impairment: 4, and depression: 2). Although several cohort studies and meta-analyses had assessed the development of cancer in diabetes, there was scant epidemiological evidence for the other conditions. Indeed, only one cohort study each had been conducted for periodontal disease, fracture, and cognitive impairment, whereas other evidence was cross-sectional, some of which was induced from baseline characteristic tables of studies designed for other purposes. Conclusion: In Japan, there is insufficient evidence about the relationship between diabetes and the incidence/prevalence of periodontal disease, fracture, cognitive impairment, and depression. By contrast, several cohort studies and integrated analyses have been conducted for the relationship with cancer. Further studies should be undertaken to estimate the contribution of diabetes on the incidence/prevalence of comorbidities that may be specific to the Japanese population.
Published: 2019
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24. Conditions, pathogenesis, and progression of diabetic kidney disease and early decliner in Japan

Author: Tomoya Mita, Yui Yoshida, Kosuke Kashiwabara, Yosuke Hirakawa, Tetsuhiro Tanaka, Shinsuke Noso, Hiroshi Ikegami, Mitsuru Ohsugi, Daisuke Koya, Koki Mise, Jun Wada, Miho Shimizu, Yumi Ito, Ichiei Narita, Naoki Kashihara, and Masaomi Nangaku
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ObjectiveGlomerular filtration rate (GFR) decreases without or prior to the development of albuminuria in many patients with diabetes. Therefore, albuminuria and/or a low GFR in patients with diabetes is referred to as diabetic kidney disease (DKD). A certain proportion of patients with diabetes show a rapid progressive decline in renal function in a unidirectional manner and are termed early decliners. This study aimed to elucidate the prevalence of DKD and early decliners and clarify their risk factors.Research design and methodsThis combination cross-sectional and cohort study included 2385 patients with diabetes from 15 hospitals. We defined DKD as a urinary albumin to creatinine ratio (ACR) ≥30 mg/gCr and/or estimated glomerular filtration rate (eGFR)
Published: 2020
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25. The Effectiveness of Liraglutide in Nonalcoholic Fatty Liver Disease Patients with Type 2 Diabetes Mellitus Compared to Sitagliptin and Pioglitazone

Author: Takamasa Ohki, Akihiro Isogawa, Masahiko Iwamoto, Mitsuru Ohsugi, Haruhiko Yoshida, Nobuo Toda, Kazumi Tagawa, Masao Omata, and Kazuhiko Koike
Subjects: Technology, Medicine, Science
Abstract: Background. Liraglutide leading to improve not only glycaemic control but also liver inflammation in non-alcoholic fatty liver disease (NAFLD) patients. Aims. The aim of this study is to elucidate the effectiveness of liraglutide in NAFLD patients with type 2 diabetes mellitus (T2DM) compared to sitagliptin and pioglitazone. Methods. We retrospectively enrolled 82 Japanese NAFLD patients with T2DM and divided into three groups (liraglutide: N = 26, sitagliptin; N = 36, pioglitazone; N = 20). We compared the baseline characteristics, changes of laboratory data and body weight. Results. At the end of follow-up, ALT, fast blood glucose, and HbA1c level significantly improved among the three groups. AST to platelet ratio significantly decreased in liraglutide group and pioglitazone group. The body weight significantly decreased in liraglutide group (81.8 kg to 78.0 kg, 𝑃
Published: 2012
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26. Trends in prescription days and intervals between physician visits and their impact on glycemic control before and during the COVID-19 pandemic in Japan.

Author: Susumu Yagome, Mitsuru Ohsugi, Takehiro Sugiyama, Ryotaro Bouchi, Atsushi Goto, and Kohjiro Ueki
Published: 2024
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27. <scp>New‐onset</scp> type 1 diabetes and Graves' disease after antiretroviral therapy in a patient with human immunodeficiency virus infection

Author: Maho Taguchi, Noriko Ihana‐Sugiyama, Daisuke Shiojiri, Kazuo Izumi, Michi Kobayashi, Noriko Kodani, Ryotaro Bouchi, Mitsuru Ohsugi, Akiyo Tanabe, Kohjiro Ueki, and Hiroshi Kajio
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine, General Medicine
Published: 2023
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28. Population-level Metagenomics Uncovers Distinct Effects of Multiple Medications on the Human Gut Microbiome

Author: Naoyoshi Nagata, Suguru Nishijima, Tohru Miyoshi-Akiyama, Yasushi Kojima, Moto Kimura, Ryo Aoki, Mitsuru Ohsugi, Kohjiro Ueki, Kuniko Miki, Eri Iwata, Kayoko Hayakawa, Norio Ohmagari, Shinichi Oka, Masashi Mizokami, Takao Itoi, Takashi Kawai, Naomi Uemura, and Masahira Hattori
Subjects: Feces, Cross-Sectional Studies, Anti-Infective Agents, Hepatology, Microbiota, Gastroenterology, Humans, Metagenomics, Fatty Acids, Volatile, Gastrointestinal Microbiome
Abstract: Medication is a major determinant of human gut microbiome structure, and its overuse increases the risks of morbidity and mortality. However, effects of certain commonly prescribed drugs and multiple medications on the gut microbiome are still underinvestigated.We performed shotgun metagenomic analysis of fecal samples from 4198 individuals in the Japanese 4D (Disease, Drug, Diet, Daily life) microbiome project. A total of 759 drugs were profiled, and other metadata, such as anthropometrics, lifestyles, diets, physical activities, and diseases, were prospectively collected. Second fecal samples were collected from 243 individuals to assess the effects of drug initiation and discontinuation on the microbiome.We found that numerous drugs across different treatment categories influence the microbiome; more than 70% of the drugs we profiled had not been examined before. Individuals exposed to multiple drugs, polypharmacy, showed distinct gut microbiome structures harboring significantly more abundant upper gastrointestinal species and several nosocomial pathobionts due to additive drug effects. Polypharmacy was also associated with microbial functions, including the reduction of short-chain fatty acid metabolism and increased bacterial stress responses. Even nonantibiotic drugs were significantly correlated with an increased antimicrobial resistance potential through polypharmacy. Notably, a 2-time points dataset revealed the alteration and recovery of the microbiome in response to drug initiation and cessation, corroborating the observed drug-microbe associations in the cross-sectional cohort.Our large-scale metagenomics unravels extensive and disruptive impacts of individual and multiple drug exposures on the human gut microbiome, providing a drug-microbe catalog as a basis for a deeper understanding of the role of the microbiome in drug efficacy and toxicity.
Published: 2022
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29. Development of Patient State Model to Overview Clinical Registry Database.

Author: Masamichi Ishii, Kengo Miyo, Takehiro Sugiyama, Mitsuru Ohsugi, and Kohjiro Ueki
Published: 2019
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30. The patient-centered diabetes management during the COVID-19 pandemic

Author: Noriko, Kodani and Mitsuru, Ohsugi
Subjects: Review, General Medicine
Abstract: Since December 2019, in the fight against the coronavirus disease 2019 (COVID-19) pandemic, we observed that glycemic control in people with diabetes is easily affected by lifestyle changes. To maintain a good health condition, a patient-centered approach with mental support and close monitoring is required. For these, telemedicine and online continuous glucose monitoring (CGM), are effective systems. Therefore, based on our experience during the two-year period, we reviewed the literature for appropriate actions required for the management of diabetes to prevent COVID-19 infection and avoid unfavorable outcomes in COVID-19 cases. Once infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is a high risk of a poor prognosis in patients with diabetes. Glucocorticoid therapy in severe COVID-19 cases leads to further hyperglycemia. Since good glycemic control has been shown to improve outcomes, strict glycemic control using CGM is recommended. Using CGM data, insulin can be adequately titrated without causing hypoglycemia, and remote data monitoring can reduce the risk of infection for health care professionals, by reducing the frequency of patient contact. Among patients with COVID-19, some are found to have newly-diagnosed diabetes at admission. Those newly diagnosed patients present with a higher risk of poor prognosis compared to those with pre-existing diabetes. Therefore, glycemic status should be evaluated in all patients with COVID-19 admitted to hospitals.
Published: 2022
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31. Clinical significance of tumor markers in patients with type 2 diabetes: a retrospective observational study

Author: Maho Taguchi, Ryotaro Bouchi, Tatsuya Fukuda, Noriko Ihana-Sugiyama, Noriko Kodani, Mitsuru Ohsugi, Akiyo Tanabe, Kohjiro Ueki, and Hiroshi Kajio
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Published: 2022
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32. Metagenomic Identification of Microbial Signatures Predicting Pancreatic Cancer From a Multinational Study

Author: Naoyoshi Nagata, Suguru Nishijima, Yasushi Kojima, Yuya Hisada, Koh Imbe, Tohru Miyoshi-Akiyama, Wataru Suda, Moto Kimura, Ryo Aoki, Katsunori Sekine, Mitsuru Ohsugi, Kuniko Miki, Tsuyoshi Osawa, Kohjiro Ueki, Shinichi Oka, Masashi Mizokami, Ece Kartal, Thomas S.B. Schmidt, Esther Molina-Montes, Lidia Estudillo, Nuria Malats, Jonel Trebicka, Stephan Kersting, Melanie Langheinrich, Peer Bork, Naomi Uemura, Takao Itoi, and Takashi Kawai
Subjects: Pancreatic Neoplasms, Feces, Hepatology, Gastroenterology, Dysbiosis, Humans, Metagenome, Metagenomics, Prospective Studies
Abstract: To identify gut and oral metagenomic signatures that accurately predict pancreatic ductal carcinoma (PDAC) and to validate these signatures in independent cohorts.We conducted a multinational study and performed shotgun metagenomic analysis of fecal and salivary samples collected from patients with treatment-naïve PDAC and non-PDAC controls in Japan, Spain, and Germany. Taxonomic and functional profiles of the microbiomes were characterized, and metagenomic classifiers to predict PDAC were constructed and validated in external datasets.Comparative metagenomics revealed dysbiosis of both the gut and oral microbiomes and identified 30 gut and 18 oral species significantly associated with PDAC in the Japanese cohort. These microbial signatures achieved high area under the curve values of 0.78 to 0.82. The prediction model trained on the Japanese gut microbiome also had high predictive ability in Spanish and German cohorts, with respective area under the curve values of 0.74 and 0.83, validating its high confidence and versatility for PDAC prediction. Significant enrichments of Streptococcus and Veillonella spp and a depletion of Faecalibacterium prausnitzii were common gut signatures for PDAC in all the 3 cohorts. Prospective follow-up data revealed that patients with certain gut and oral microbial species were at higher risk of PDAC-related mortality. Finally, 58 bacteriophages that could infect microbial species consistently enriched in patients with PDAC across the 3 countries were identified.Metagenomics targeting the gut and oral microbiomes can provide a powerful source of biomarkers for identifying individuals with PDAC and their prognoses. The identification of shared gut microbial signatures for PDAC in Asian and European cohorts indicates the presence of robust and global gut microbial biomarkers.
Published: 2022
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33. Left Hemiplegia Possibly Due to Glucose Reperfusion Injury after Recovery of Severe Hypoglycemia in a Woman with Type 2 Diabetes Mellitus

Author: Akiyo Tanabe, Mitsuru Ohsugi, Tetsuro Tsujimoto, Hiroshi Kajio, Ryotaro Bouchi, Kohjiro Ueki, Noritoshi Arai, and Erika Sugito
Subjects: medicine.medical_specialty, Internal capsule, medicine.medical_treatment, Hemiplegia, Type 2 diabetes, Internal medicine, Internal Medicine, medicine, Humans, Aged, Hypoglycemic encephalopathy, medicine.diagnostic_test, business.industry, Insulin, Type 2 Diabetes Mellitus, Magnetic resonance imaging, General Medicine, medicine.disease, Magnetic Resonance Imaging, Hypoglycemia, Hyperintensity, Glucose, Diabetes Mellitus, Type 2, Reperfusion Injury, Cardiology, Female, business, Reperfusion injury
Abstract: A 79-year-old woman with type 2 diabetes receiving insulin was rushed to our hospital due to severe hypoglycemia. Glucose was administered, and the consciousness disturbance was promptly improved. A few hours later, conjugate deviation of the eyes to the right and left hemiplegia occurred at a normal glucose level. Cerebral magnetic resonance imaging showed hyperintensities of the right posterior limb of the internal capsule and the medial thalamus on diffusion-weighted imaging sequences. However, the changes observed using magnetic resonance imaging disappeared completely on the third day, and her symptoms subsequently improved. This may have been a case of glucose reperfusion injury.
Published: 2022
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34. Retrospective nationwide study on the trends in first‐line antidiabetic medication for patients with type 2 diabetes in Japan

Author: Takehiro Sugiyama, Atsushi Goto, Noriko Ihana-Sugiyama, Ryotaro Bouchi, Toshimasa Yamauchi, Kohjiro Ueki, Takashi Kadowaki, Kenjiro Imai, and Mitsuru Ohsugi
Subjects: Drug, medicine.medical_specialty, medicine.drug_class, Type 2 diabetes, Endocrinology, Diabetes and Metabolism, media_common.quotation_subject, First line, Diseases of the endocrine glands. Clinical endocrinology, Japan, First‐line therapy, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Health insurance, Humans, Hypoglycemic Agents, Medical prescription, Antidiabetic agents, Retrospective Studies, media_common, Dipeptidyl-Peptidase IV Inhibitors, Biguanide, business.industry, General Medicine, medicine.disease, RC648-665, Diabetes Mellitus, Type 2, business
Abstract: Aims/Introduction To investigate the national trend in the prescription of first‐line non‐insulin antidiabetic agents and total medical costs (TMCs) after prescribing the drug in Japanese patients with type 2 diabetes. Materials and Methods Using the National Database of Health Insurance Claims and Specific Health Check‐ups of Japan covering almost the entire Japanese population, we calculated the proportion of each antidiabetic drug from 2014 to 2017, and determined the factors associated with drug selection. The TMCs in the first year after starting the drugs were calculated, and factors associated with the costs were also determined. Results Among 1,136,723 new users of antidiabetic agents, dipeptidyl peptidase‐4 inhibitors were the most prescribed (65.1%), followed by biguanides (15.9%) and sodium–glucose cotransporter 2 inhibitors (7.6%). Sodium–glucose cotransporter 2 inhibitor and biguanide use increased during 2014–2017 (2.2%–11.4% and 13.7%–17.2%, respectively), whereas the others decreased. Biguanides were not prescribed at all in 38.2% of non‐Japan Diabetes Society‐certified facilities. The TMCs were the lowest among those who started with biguanides. Fiscal year, age, sex, facility, number of beds and comorbidities were associated with drug choice and TMCs. There were wide regional variations in the drug choice, but not in the TMCs. Conclusions Unlike in the USA and Europe, dipeptidyl peptidase‐4 inhibitor is the most prescribed first‐line medication for type 2 diabetes patients in Japan, while there is a wide variation in the drug choice by facility‐type and prefecture.
Published: 2022

35. Incidence of interventions for diabetic retinopathy and serious lower-limb complications and its related factors in patients with type 2 diabetes using a real-world large claims database

Author: Ayako Yanagisawa-Sugita, Takehiro Sugiyama, Noriko Ihana-Sugiyama, Hirokazu Tanaka, Kenjiro Imai, Kohjiro Ueki, Mitsuru Ohsugi, Nanako Tamiya, and Yasuki Kobayashi
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine, Original Article
Abstract: AIMS: To examine the incidence of interventions for diabetic retinopathy and serious limb complications and to elucidate the patient attributes related to the incidence of each intervention based on real-world claims data from Japan. MATERIALS AND METHODS: A retrospective longitudinal study design involving a 9 year (2009–2018) claims database obtained from the JMDC Inc. Patients with type 2 diabetes aged 20–74 years taking antidiabetic medications were divided into two groups: “patients with newly initiated antidiabetic medication” (Group 1, n = 47,201) and “patients with continuing antidiabetic medication” (Group 2, n = 82,332). The incidence rate for each intervention was analyzed. We also divided Group 1 into the former and latter periods and investigated temporal changes. RESULTS: The incidences of the first retinopathy intervention (laser photocoagulation, vitrectomy, or intraocular injection), vitrectomy, and lower-limb amputations in Group 1 were 7.46, 2.37, and 0.31 /1000 person-years, respectively. Those in Group 2 were about 1.2–1.5 times higher. Older age, insulin use, and being dependents rather than insured persons were associated with a higher incidence in both groups after adjustment. While the incidence of the interventions for retinopathy hardly changed during the observation period, that of lower-limb amputations decreased by 40%, with less statistical significance (p = 0.11). CONCLUSIONS: We showed the incidences of the first retinopathy interventions and lower-limb amputations and their secular trends in patients with diabetes, stratified by whether the antidiabetic medication was newly initiated or not. Older age, insulin use, and being dependents were risk factors of these interventions for diabetic complications. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00566-7.
Published: 2022
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36. Understanding the quality of diabetes care in Japan

Author: Takehiro Sugiyama, Hirokazu Tanaka, Robert A. Gabbay, Mitsuru Ohsugi, and Joanna Mitri
Subjects: medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, media_common.quotation_subject, 030209 endocrinology & metabolism, Review Article, Intermediate outcome, 030204 cardiovascular system & hematology, Lipid screening, medicine.disease, Nephropathy screening, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal Medicine, medicine, Quality (business), Performance measurement, Quality of care, Intensive care medicine, business, media_common, Healthcare system
Abstract: BACKGROUND: Among chronic diseases, diabetes is a frequent focus of performance measurement. Disease-specific indicators based on evidence-based clinical guidelines have been used to evaluate the quality of care. There are worldwide efforts to improve the quality of diabetes care. Measuring the gap is an essential first step toward improving the quality of care. METHODS: In order to better understand the status of quality of diabetes care in Japan, a country with a universal healthcare system, we performed a literature search looking for all studies reporting on quality indicators. In this review, we summarized the studies that have looked at the status of the quality of diabetes care over the last decade. RESULTS: There were a total of 6 studies that reported on process including HbA1c, blood pressure, lipid screening, retinopathy and nephropathy screening and intermediate clinical measures which included percentages of patients reaching targets for HbA1c, blood pressure and LDL-C. Overall, the process measures continue to improve, however the clinical intermediate outcome measures remain suboptimal. CONCLUSION: Despite the improvement in diabetes related process measures, there is limited data on clinical measures. It is necessary to shed more light on the assessment of the quality of diabetes care.
Published: 2022
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37. Empagliflozin in Patients with Chronic Kidney Disease

Author: Herrington, William G, Staplin, Natalie, Wanner, Christoph, Green, Jennifer B, Hauske, Sibylle J, Emberson, Jonathan R, Preiss, David, Judge, Parminder, Mayne, Kaitlin J, Ng, Sarah Y A, Sammons, Emily, Zhu, Doreen, Hill, Michael, Stevens, Will, Wallendszus, Karl, Brenner, Susanne, Cheung, Alfred K, Liu, Zhi-Hong, Li, Jing, Hooi, Lai Seong, Liu, Wen, Kadowaki, Takashi, Nangaku, Masaomi, Levin, Adeera, Cherney, David, Maggioni, Aldo P, Pontremoli, Roberto, Deo, Rajat, Goto, Shinya, Rossello, Xavier, Tuttle, Katherine R, Steubl, Dominik, Petrini, Michaela, Massey, Dan, Eilbracht, Jens, Brueckmann, Martina, Landray, Martin J, Baigent, Colin, Haynes, Richard, The EMPA-KIDNEY Collaborative Group: Colin Baigent, Martin J Landray, Christoph Wanner, William G Herrington, Richard Haynes, Jennifer B Green, Sibylle J Hauske, Martina Brueckmann, Mark Hopley, Maximillian von-Eynatten, Jyothis George, Susanne Brenner, Alfred K Cheung, David Preiss, Zhi-Hong Liu, Jing Li, Laiseong Hooi, Wen Liu, Takashi Kadowaki, Masaomi Nangaku, Adeera Levin, David Cherney, Roberto Pontremoli, Aldo P Maggioni, Natalie Staplin, Jonathan Emberson, Stefan Hantel, Shinya Goto, Rajat Deo, Katherine R Tuttle, Michael Hill, Parminder Judge, Kaitlin J Mayne, Sarah Y A Ng, Xavier Rossello, Emily Sammons, Doreen Zhu, Peter Sandercock, Rudolf Bilous, Charles Herzog, Paul Whelton, Janet Wittes, Derrick Bennett, Patricia Achiri, Chrissie Ambrose, Cristina Badin, Jill Barton, Richard Brown, Andy Burke, Sebastian Butler, Rejive Dayanandan, Pia Donaldson, Robert Dykas, Lucy Fletcher, Kate Frederick, Hannah Kingston, Mo Gray, Emily Harding, Akiko Hashimoto, Lyn Howie, Susan Hurley, Ryonfa Lee, Nik Luker, Kevin Murphy, Mariko Nakahara, John Nolan, Michelle Nunn, Sorcha Mulligan, Akiko Omata, Sandra Pickworth, YanRu Qiao, Shraddha Shah, Karen Taylor, Alison Timadjer, Monique Willett, Liz Wincott, Qin Yan, Hui Yu, Louise Bowman, Fang Chen, Robert Clarke, Michelle Goonasekera, Waseem Karsan, Marion Mafham, Christina Reith, Mohammed Zayed, Ritva Ellison, Rowan Moys, Will Stevens, Kevin Verdel, Karl Wallendszus, Chris Bowler, Anna Brewer, Andy Measor, Guanguo Cui, Charles Daniels, Angela Field, Bob Goodenough, Ashley Lawson, Youcef Mostefai, Dheeptha Radhakrishnan, Samee Syed, Shuang Xia, Ruth Adewuyi-Dalton, Thomas Arnold, Anne-Marie Beneat, Anoushka Bhatt, Chloe Bird, Andrew Breach, Laura Brown, Mark Caple, Tatyana Chavagnon, Karen Chung, Sarah Clark, Luminita Condurache, Katarzyna Eichstadt, Marta Espino Obrero, Scarlett Forest, Helen French, Nick Goodwin, Andrew Gordon, Joanne Gordon, Cat Guest, Tina Harding, Michal Hozak, Matthew Lacey, David MacLean, Louise Messinger, Stewart Moffat, Martin Radley, Claire Shenton, Sarah Tipper, Jon Tyler, Lesley Weaving, James Wheeler, Elissa Williams, Tim Williams, Hamish Woodhouse, Angela Chamberlain, Jo Chambers, Joanne Davies, Denise Donaldson, Pati Faria-Shayler, Denise Fleming-Brown, Jennifer Ingell, Carol Knott, Anna Liew, Helen Lochhead, Juliette Meek, Isabel Rodriguez-Bachiller, Andrea Wilson, Patrick Zettergren, Rach AitSadi, Ian Barton, Alex Baxter, Yonghong Bu, Lukasz Danel, Sonja Grotjahn, Rijo Kurien, Michael Lay, Archie Maskill, Aleksandra Murawska, Rachel Raff, Allen Young, Rebecca Sardell, Vladimir Cejka, Marcela Fajardo-Moser, Christian Hartner, Doris Poehler, Janina Renner, Franziska Scheidemantel, Miya Bryant, Anita Hepditch, Cassandra Johnson, Erin Latore, Yolanda Miller, Lauren Price, Merilee Whalen, Ashleigh Wheeler, Jenny Ingell, Yu An, Yinghua Chen, Peiling Chen, Hao Dai, Hong Du, Fang Feng, Qing Guo, Libo Hou, Wuhanbilige Hundei, Binbin Jin, Yan Li, Jiamin Liu, Xia Song, Yanping Wang, Yanwu Yu, Ning Zhang, Lingshan Zhao, Hui Zhong, Cheng Beng Goh, Ye Mun Low, Soon Yi Sor, Farah Hanis Zulkipli, Sarojini Sivanandam, Natsuki Arai, Ai Fukasawa, Mizue Furukawa, Keisuke Habuki, Shoko Hayashi, Wakako Isari, Saki Kanegae, Maria Kawai, Reiki Kobayashi, Takako Kuramae, Chika Kuribayashi, Sawako Maeno, Satoshi 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Kunihiro Yamagata, Rikako Nakamura, Aiko Yamada, Mitsuru Ohsugi, Motoharu Awazawa, Ryotaro Bouchi, Shota Hashimoto, Makiko Hashimoto, Tomoko Hisatake, Noriko Ihana, Koko Ishizuka, Kazuo Izumi, Hiroshi Kajio, Michi Kobayashi, Noriko Kodani, Koji Maruyama, Michihiro Matsumoto, Maya Matsushita, Tomoka Nakamura, Takehiro Sugiyama, Akiyo Tanabe, Aiko Terakawa, Kojiro Ueki, Yuko Orimo, Takako Ozawa, Eriko Takahira, Yoshimitsu Yamasaki, Masakazu Haneda, Tadahiro Tomita, Saori Akimoto, Akihiro Fujimoto, Kenji Ishihara, Chiho Murakami, Akiyo Nishiyama, Yukiko Toyonaga, Kana Uozumi, Yukihiro Yamaji, Tetsuya Shigehara, Jun Okajyo, Yukihiro Shimizu, Shingo Iwasaki, Yuki Fukao, Megumi Furusho, Shintaro Nunokawa, Hideki Katagiri, Tomohito Izumi, Keizo Kaneko, Shinjiro Kodama, Mariko Miyazaki, Yuichiro Munakata, Tasuku Nagasawa, Yuji Oe, Hiroto Sugawara, Kei Takahashi, Kazushige Hirata, Keiko Inomata, Shoko Otomo, Taeko Uchida, Chigusa Yamashita, Arihiro Kiyosue, Ryota Tamura, Francois Dube, Marilene Bolduc, Marie-Christine Talbot, Leslie Cham, Vesta Lai, Josephine Tse, Shivinder Jolly, Tabbatha Duck, Scott Lyle, Rachel Epp, Camille Galloway, Susan Haskett, Elizabeta Matvienko, Liam Paulsen, Louise Moist, Zabrina Lozon, Tina Ramsey, Brittany Whitmore, Bader Al-Zeer, Paula Macleod, Aoife O'Sullivan, Zainab Sheriff, Sam Tholl, Amritanshu Pandey, Samantha Armstrong, Bethelihem Gebeyehu, Patrick Toth, Ronald Goldenberg, Mahsa Jahangiriesmaili, Shariff Sanguila, Neethi Suresh, Tanvi Talsania, Nadia Zalunardo, Mohsen Agharazii, Marie-Pier Roussel, Annie Saillant, France Samson, Harpreet Bajaj, Miken Bhavsar, Parul Dhall, Gagandeep Dhillon, Bhupinder Grewal, Taniya Nimbkar, Francois Madore, Guylaine Marcotte, Oren Steen, Mathura Bullen, Shayani Raguwaran, Andre Valleteau, Marie-France Langlois, Christine Brown, Andrew Steele, Melissa Garrity, Taneera Ghate, Holly Robinson, Michael Tolibas, Chetna Tailor, Lauren Elliott, Christine McClary-Wright, Fadia Boreky, Sameh Fikry, Ayesha Ali, Chintankumar Barot, Wagdy Basily, Thisun Saram, Vinay Varad, Hasnain Khandwala, Alex Aguilera, Patricia Alvarez, Balwinder Gill, Nazihah Huda, Aamir Navivala, Daniel Pinto, Micheli Bevilacqua, Elaine Fung, Geraldine Hernandez, Puneet Mann, Jaskiran Saini, Remi Rabasa-Lhoret, Danijela Bovan, Marie Devaux, Cecilia Barnini, Giovanna Leoncini, Luca Manco, Giulia Nobili, Matteo Piemontese, Filippo Aucella, Rachele Grifa, Francesco Totaro, Gaetano La Manna, Irene Capelli, Giuseppe Cianciolo, Sarah Lerario, Fulvia Zappulo, Alberto Rosati, Filippo Fani, Giuseppe Spatoliatore, Loreto Gesualdo, Francesco Pesce, Maria Russo, Maria Zippo, Cesira Cafiero, Daria Motta, Simona Bianco, Donatella Bilucaglia, Piergiorgio Messa, Laura Pavone, Federica Tripodi, Simone Vettoretti, Paola Fioretto, Gianni Carraro, Filippo Farnia, Anna Postal, Alessandro D'Amelio, Antonio Cardone, Giovanni Piccinni, Annalisa Aloisi, Francesco Scolari, Federico Alberici, Alice Guerini, Chiara Saccà, Chiara Salviani, Roberta Zani, Luca De Nicola, Carlo Garofalo, Maria Elena Liberti, Roberto Minutolo, Luigi Pennino, Lucio Polese, Paolo Mené, Simona Barberi, Clorinda Falcone, Francesco Russo, Maurizio Caroppo, Gennaro Santorelli, Rodolfo Rivera, Domenico Santoro, Alfio Giuffrida, Fortunata Zirino, Cristina Calvi, Luca Estienne, Giovanni Gambaro, Concetta Gangemi, Vittorio Ortalda, Giuseppina Pessolano, Giuseppe Grandaliano, Rocco Baccaro, Pietro Ferraro, Roberto Mangiacapra, Marco Melandri, Nadia Foligno, Rita Quartagno, Giuseppe Vezzoli, Elena Brioni, William G, Herrington, Natalie, Staplin, Christoph, Wanner, Jennifer B, Green, Sibylle J, Hauske, Jonathan R, Emberson, David, Prei, Parminder, Judge, Kaitlin J, Mayne, Sarah Y A, Ng, Emily, Sammon, Doreen, Zhu, Michael, Hill, Will, Steven, Karl, Wallendszu, Susanne, Brenner, Alfred K, Cheung, Zhi-Hong, Liu, Jing, Li, Lai Seong, Hooi, Wen, Liu, Takashi, Kadowaki, Masaomi, Nangaku, Adeera, Levin, David, Cherney, Aldo P, Maggioni, Roberto, Pontremoli, Rajat, Deo, Shinya, Goto, Xavier, Rossello, Katherine R, Tuttle, Dominik, Steubl, Michaela, Petrini, Dan, Massey, Jens, Eilbracht, Martina, Brueckmann, Martin J, Landray, Colin, Baigent, Richard, Hayne, EMPA-KIDNEY Collaborative Group: Colin Baigent, The, J Landray, Martin, Wanner, Christoph, G Herrington, William, Haynes, Richard, B Green, Jennifer, J Hauske, Sibylle, Brueckmann, Martina, Hopley, Mark, von-Eynatten, Maximillian, George, Jyothi, Brenner, Susanne, K Cheung, Alfred, Preiss, David, Liu, Zhi-Hong, Li, Jing, Hooi, Laiseong, Liu, Wen, Kadowaki, Takashi, Nangaku, Masaomi, Levin, Adeera, Cherney, David, Pontremoli, Roberto, P Maggioni, Aldo, Staplin, Natalie, Emberson, Jonathan, Hantel, Stefan, Goto, Shinya, Deo, Rajat, R Tuttle, Katherine, Hill, Michael, Judge, Parminder, J Mayne, Kaitlin, A Ng, Sarah Y, Rossello, Xavier, Sammons, Emily, Zhu, Doreen, Sandercock, Peter, Bilous, Rudolf, Herzog, Charle, Whelton, Paul, Wittes, Janet, Bennett, Derrick, Achiri, Patricia, Ambrose, Chrissie, Badin, Cristina, Barton, Jill, Brown, Richard, Burke, Andy, Butler, Sebastian, Dayanandan, Rejive, Donaldson, Pia, Dykas, Robert, Fletcher, Lucy, Frederick, Kate, Kingston, Hannah, Gray, Mo, Harding, Emily, Hashimoto, Akiko, Howie, Lyn, Hurley, Susan, Lee, Ryonfa, Luker, Nik, Murphy, Kevin, Nakahara, Mariko, Nolan, John, Nunn, Michelle, Mulligan, Sorcha, Omata, Akiko, Pickworth, Sandra, Qiao, Yanru, Shah, Shraddha, Taylor, Karen, Timadjer, Alison, Willett, Monique, Wincott, Liz, Yan, Qin, Yu, Hui, Bowman, Louise, Chen, Fang, Clarke, Robert, Goonasekera, Michelle, Karsan, Waseem, Mafham, Marion, Reith, Christina, Zayed, Mohammed, Ellison, Ritva, Moys, Rowan, Stevens, Will, Verdel, Kevin, Wallendszus, Karl, Bowler, Chri, Brewer, Anna, Measor, Andy, Cui, Guanguo, Daniels, Charle, Field, Angela, Goodenough, Bob, Lawson, Ashley, Mostefai, Youcef, Radhakrishnan, Dheeptha, Syed, Samee, Xia, Shuang, Adewuyi-Dalton, Ruth, Arnold, Thoma, Beneat, Anne-Marie, Bhatt, Anoushka, Bird, Chloe, Breach, Andrew, Brown, Laura, Caple, Mark, Chavagnon, Tatyana, Chung, Karen, Clark, Sarah, Condurache, Luminita, Eichstadt, Katarzyna, Espino Obrero, Marta, Forest, Scarlett, French, Helen, Goodwin, Nick, Gordon, Andrew, Gordon, Joanne, Guest, Cat, Harding, Tina, Hozak, Michal, Lacey, Matthew, Maclean, David, Messinger, Louise, Moffat, Stewart, Radley, Martin, Shenton, Claire, Tipper, Sarah, Tyler, Jon, Weaving, Lesley, Wheeler, Jame, Williams, Elissa, Williams, Tim, Woodhouse, Hamish, Chamberlain, Angela, Chambers, Jo, Davies, Joanne, Donaldson, Denise, Faria-Shayler, Pati, Fleming-Brown, Denise, Ingell, Jennifer, Knott, Carol, Liew, Anna, Lochhead, Helen, Meek, Juliette, Rodriguez-Bachiller, Isabel, Wilson, Andrea, Zettergren, Patrick, Aitsadi, Rach, Barton, Ian, Baxter, Alex, Bu, Yonghong, Danel, Lukasz, Grotjahn, Sonja, Kurien, Rijo, Lay, Michael, Maskill, Archie, Murawska, Aleksandra, Raff, Rachel, Young, Allen, Sardell, Rebecca, Cejka, Vladimir, Fajardo-Moser, Marcela, Hartner, Christian, Poehler, Dori, Renner, Janina, Scheidemantel, Franziska, Bryant, Miya, Hepditch, Anita, Johnson, Cassandra, Latore, Erin, Miller, Yolanda, Price, Lauren, Whalen, Merilee, Wheeler, Ashleigh, Ingell, Jenny, An, Yu, Chen, Yinghua, Chen, Peiling, Dai, Hao, Du, Hong, Feng, Fang, Guo, Qing, Hou, Libo, Hundei, Wuhanbilige, Jin, Binbin, Li, Yan, Liu, Jiamin, Song, Xia, Wang, Yanping, Yu, Yanwu, Zhang, Ning, Zhao, Lingshan, Zhong, Hui, Beng Goh, Cheng, Mun Low, Ye, Yi Sor, Soon, Hanis Zulkipli, Farah, Sivanandam, Sarojini, Arai, Natsuki, Fukasawa, Ai, Furukawa, Mizue, Habuki, Keisuke, Hayashi, Shoko, Isari, Wakako, Kanegae, Saki, Kawai, Maria, Kobayashi, Reiki, Kuramae, Takako, Kuribayashi, Chika, Maeno, Sawako, Masumoto, Satoshi, Morisaki, Tomoko, Oda, Minoru, Sawada, Kazue, Sugamori, Kenta, Tatsuzawa, Ayana, Tomita, Aiko, Yuasa, Kazuyuki, Inazawa, Hiroko, Axler, Amanda, Gallo, Kerri, Baldini, Ester, Bartolomei Mecatti, Barbara, Bianchini, Francesca, Ceseri, Martina, Cipressa, Laura, Fabbri, Gianna, Lorimer, Andrea, Lucci, Donata, Ghavampour, Sharang, Knoppe, Anja, Schmidt-Gurtler, Han, Dumann, Hubert, Merscher, Sybille, Patecki, Margret, Rainer Schlieper, Georg, Torp, Anke, Weber, Bianca, Zietz, Maja, Hohenstein, Bernd, Benck, Ur, Draganova, Diliana, Weinreich, Thoma, Wolf, Lothar, Gaidu, Jasmine, Reiner, Hanna, Visnjic, Mandy, Steffl, Daniel, Breitenfeldt, Marie, Kraemer-Guth, Annette, Braun, Christine, Hagge, Simone, Schomig, Michael, Matthias, Stephan, Stoffler, Dominik, Schumacher, Beate, Sitter, Thoma, Fuessl, Louise, Krappe, Julia, Loutan, Jerome, Vielhauer, Volker, Andriaccio, Luciano, Maurer, Magdalena, Winkelmann, Bernhard, Dursch, Martin, Seifert, Linda, Tenbusch, Linda, Weinmann-Menke, Julia, Boedecker, Simone, Kaluza-Schilling, Wiebke, Kraus, Daniel, Krieger, Carina, Schmude, Margit, Schreiber, Anne, Eckrich, Ewelina, Tschope, Diethelm, Arbi, Abdulwahab, Lee-Barkey, Young, Stratmann, Bernd, Prib, Natalie, Rolfsmeier, Sina, Schneider, Irina, Rump, Lar, Stegbauer, Johanne, Pötz, Christine, Schemmelmann, Mara, Schmidt, Claudia, Koch, Michael, Aker, Sendogan, Küpper, Annika, Martin, Manuela, Pfab, Thiemo, Albert, Christian, Haase, Michael, Zander, Barbara, Schneider-Danwitz, Claudia, Seeger, Wolfgang, Seeger, Wolf-Adam, Zemann, Britta, Stellbrink, Christoph, Marx, Kristin, Stellbrink, Ekaterina, Brettschneider, Britta, Watson, Stephanie, Iselt, Marion, Klausmann, Gerhard, Kummer, Inga-Nadine, Kutschat, Auguste, Streitenberger, Simone, Girndt, Matthia, Markau, Silke, Girakossyan, Ina, Hanf, Claudia, Beige, Joachim, Wendt, Ralph, Schmidt, Ulrike, Schneider, Andrea, Veelken, Roland, Donhauser, Claudia, Becker, Lui, Miftari, Nexhat, Wolfling, Ricarda, Morlok, Sarah, Hugo, Christian, Paliege, Alexander, Passauer, Jen, Stumpf, Julian, Fleischer, Annegret, Haaser, Kerstin, Kraemer, Bernhard, Jochims, Jan, Kruger, Bernd, Foellinger, Claudia, Reisler, Anastassiya, Strutz, Frank, Haack, Stefan, Hohenstatt, Ursula, Busch, Martin, Herfurth, Konstantin, Wolf, Gunter, Paul, Rainer, Haller, Hermann, Kaufeld, Jessica, Menne, Jan, Bahlmann-Kroll, Elisabeth, Bergner, Angela, Weihprecht, Horst, Er, Aydin, Sonntag, Florian, Turan, Elif, Wittmann, Michael, Klauser, Franziska, Voigt, Eva, Schettler, Volker, Schulz, Egbert, Rohnstock, Madlen, Schettler, Elke, Schroppel, Bernd, van Erp, Rene, Kachele, Martin, Ludwig, Ulla, Schulte-Kemna, Lena, Kmietschak, Waltraud, Preiss, Elke, Ruocco, Martina, Heine, Gunnar, Brzoska, Martin, Gabel, Sebastian, Büttner, Christina, Sabarai, Asma, Banas, Bernhard, Bergler, Tobia, Ehrl, Yvonne, Putz, Franz, Schuster, Antonia, Kuhn, Stefanie, Schramm, Torsten, Degenhardt, Stefan, Schmidt, Gerhard, Weiland, Lea, Giebeln-Hudnell, Ulrike, Kielstein, Jan, Eden, Gabriele, Fuchs, Brigitte, Morig, Gina, Winkler, Manuela, Darius, Harald, Kriatselis, Charalampo, Roesch, Carl-Philipp, Maselli, Astrid, Alscher, Dominik, Ketteler, Marku, Schanz, Moritz, Schricker, Severin, Rettenmaier, Bianka, Schwab, Andrea, Pergola, Pablo, Leal, Irene, Cagle, Melissa, Romo, Anna, Torres, Anthony, Joshi, Sucharit, Barrett, Kulli, Africano, Alexi, Dodds, Vicki, Gowen, Dorleena, Morris, Ashlee, Fernandez, Juan, Jimenez, Guillermo, Viera, Ricardo, Bruce, Kendaling, Barrios, Ryan, Garcia, Maylin, Garcia, Kerelyn, Leal, Iradi, Tietjen, David, Bains, David, Castillo, Carlo, Brewer, Genielle, Davis, Justin, Freking, Natalie, Golson, Brittany, Ham, Sally, Roesch, Jesslyn, Suchinda, Pusadee, Beigh, Shameem, Lilavivat, Usah, Bilton, Joyce, Bocchicchia, Kim, Turner, Jeffrey, Dahl, Neera, Peixoto, Aldo, Kavak, Yasemin, Liberti, Lauren, Nair, Hari, Page, Nicola, Rosenberg, Stephanie, Simmons, Kathryn, Isakova, Tamara, Frazier, Rebecca, Mehta, Rupal, Srivastava, Anand, Fox, Patrick, Hecktman, Jonathan, Hodakowski, Alexander, Martinez, Carlo, Phillips, Rachel, Stevenson, Alexi, Mustafa, Reem, Jansson, Kyle, Kimber, Cassandra, Stubbs, Jason, Tuffaha, Ahmad, Yarlagadda, Sri, Griffin, Debbie, Laundy, Elisabeth, Tang, Zhuo, Alicic, Radica, Cooper, Ann, Davis, Lisa, Gore, Ashwini, Goldfaden, Rebecca, Harvill, Leslie, Hichkad, Lisa, Johns, Barry, Jones, Thoma, Merritt, Kayla, Sheldon, Jennifer, Stanfield, Jennifer, Alexander, Lindsay, Preston, Kaitlyn, Wood, Lindsey, Pradhan, Rajesh, Deraad, Roger, Mcintosh, Kelli, Raymond, Loui, Shepperd, Michael, Mclaughlin, Susan, Seifert, Mary, Shepherd, Andrew, Aiello, Joseph, Durham, William, Loudermilk, Laurie, Manley, John, Burnette, Sabrina, Evans, Stephanie, Johnson, Tara, Sloan, Lance, Ann Acosta, Judy, Gillham, Stacy, Sloan, Katia, Squyres, Sueann, Rocco, Michael, Hawfield, Amret, Bagwell, Ben, Richmond, Lauren, Soufer, Joseph, Clarke, Subha, Aliu, Amanda, Calabrese, Kristine, Davis, Amanda, Poma, Veronica, Spinola, Tracy, Magee, Jame, Silva, Ricardo, Choksi, Rushab, Dajani, Lorraine, Evans, John, George, Anil, Krish, Prasanth, Martins, Gerard, Sheikh-Ali, Mae, Sutton, David, Driver, Freda, Hanburry, Abraham, Hume, Laura, Hurst, Amber, Taddeo, Matthew, Turner, Marla, Yousif, Veronica, Beddhu, Srinivasan, Al-Rabadi, Laith, Abraham, Nikita, Caamano, Amalia, Carle, Judy, Gonce, Victoria, Staylor, Kaitlyn, Zhou, Na, Bansal, Shweta, Bhattarai, Manoj, Sharma, Kumar, Debnath, Subrata, Garza, Aliseiya, Velagapudi, Chakradhar, Rovner, Sergio, Almeida, Javier, Casares, Pablo, Stewart-Ray, Verlaine, Almaraz, Rene, Dayrell, Renata, Moncada, Ana, Pulido, Ricardo, Rodriquez, Roxana, Deeb, Wasim, Degoursey, Kathryn, Gloria, Rodel, Greene, Trevor, Miller, Robert, Pereira, Edward, Roura, Miguel, Domingo, Debbie, Dorestin, Sasha, Hodge, William, Jackson, Cathy, Lund, Deborah, Taylor, Katrina, Boren, Kenneth, Cleveland, Brittany, Gaiser, Sandra, Sahani, Mandeep, Aldrich, Logan, Edmerson, Exodu, Limon, Edmond, Valletta, Cole, Vasquez, Patricia, Provenzano, Christopher, Brar, Navkiranjot, Henderson, Heather, Keith, Bellovich, Khai, Qur, Khairullah, Quresh, Makos, Gail, Topf, Joel, Gasko, Sherry, Henschel, Rosemarie, Knapp, Kaitlin, Kozlowski, Teresa, Lafleur, Paula, Varughese, Ashwathy, Xue, Hui, Wu, Patricia, Arechiga, Olga, Darbeau, Shan, Fechter, Michael, Martinez, Stephanie, Hanson, Lenita, Cooper, Nyla, Madera, Areli, Cadorna, Jay, Sheridan, Rita, Sparks, Helen, Eilerman, Bradley, Bodine, Susanne, Eid, Wael, Flora, Rebecca, Avery, Amber, Hardy, Cashmere, Biscoveanu, Mihaela, Nagelberg, Steven, Cummins, Tracey, Rahbari-Oskoui, Frederic, Oommen, Anju, Forghani, Zohreh, Hitchcock, Stacie, Hosein, Darya, Watkins, Diane, Patel, Minesh, Lambert, Anthony, Newman, Elizabeth, Wood, Autumn, Ross, Tammy, Topping, Stephany, Mulhern, Jeffrey, Murphy, Lorna, Vasseur, Ann, Greenwood, Gregory, Hadley, Alexander, Laurienti, Denise, Marshall, Christopher, Mclean, Nichola, Satko, Scott, Caudill, Brandy, Maris, Jacob, Rogers, Janice, Vanhoy, Cindy, Thomas, George, Nakhoul, George, O'Toole, John, Taliercio, Jonathan, Cooperman, Leslie, Markovic, Marina, Tucky, Barbara, Dev, Devasmita, Hasan, Alia, Yalamanchili, Hima, Jain, Namita, Mcneil, Lesley, Wines, Eric, Park, Jean, Ghazi, Adline, Hamm, Mia, Patel, Teja, Mottl, Amy, Chang, Emily, Derebail, Vimal, Cole, Emmie, Froment, Anne, Kelley, Sara, Osmond Foster, Jordan, Mahabadi, Vahid, Jafari, Golriz, Kamarzarian, Anita, Arriaga, Wendy, Arteaga, Daisy, Machicado, Rosario, Naverrete, Genesi, Kumar, Prashant, Nazeer, Imran, Urquia, Karina, Glider, Tammi, Jones, Vickie, Rucker, Savannah, Wiley, Jennifer, Pandey, Rahul, Arroyo, Jesu, Pariani, Harish, Ahmad, Mohammad, Mozaffari, Shahin, Perez, Erika, Budoff, Matthew, Roy, Sion, Birudaraju, Divya, Ghanem, Ahmed, Hamal, Sajad, Aronoff, Stephen, Joye Petr, Elisa, Sachson, Richard, Wiebel, Jaime, Akram, Sana, Jones, Laurie, Knight, Curti, Tarlac, Maurie, Ahmed, Shahbaz, Szerlip, Harold, Akinfolarin, Akinwande, Mehta, Ankit, Camp, Shana, Castro, Cindy, Cooper, Zanaida, Terry, Jessica, Awad, Ahmed, Kothapalli, Bhavya, Lustig, Ryan, Alfaress, Serine, Jasim, Hyder, Parrigon, Mary, Karounos, Denni, Ahmed, Sadiq, Berry, Maggie, Oremus, Ruth, Hernandez-Cassis, Carlo, Ugwu, Elia, Junejo, Nazia, Suazo, Nancy, Segal, Mark, Kazory, Amir, Brown, Sherry, Daniels, Tristan, Dayi, Sofia, Hogan, Renee, Mccray, Kathy, Stickley, Jennifer, Rahman, Mahboob, Dobre, Mirela, Negrea, Lavinia, Padiyar, Aparna, Pradhan, Nishigandha, Rashidi, Arash, Sarabu, Nagaraju, Donley, Vicki, Young, Tricia, Oguchi, Godson, Onyema, Judepatrick, Damianik, Kahla, Dienes, Jack, Plummer-Morgan, Judith, Roman, Marilyn, Skipper, Mauver, Villaruel, Stacey-Ann, Williams, Krystle, Sugimoto, Danny, Dugas, Jeffrey, Ahmed, Ismeal, Bhairoo, Jamie, Rijos, Dolore, Salim, Huzaifa, Gavrila, Madita, Lafferty, Kathryn, Rabara, Ria, Ruse, Sally, Weetman, Maria, Bushnell, Jame, Power, Albert, Jenkins, Alison, Jones, Stefanie, Scott, Amanda, Byrne, Cath, Jesky, Mark, Cowley, Alison, Mchaffie, Emma, Waterfall, Holly, Taylor, Jo, Bough, Laura, Phillips, Thoma, Winter-Goodwin, Barbara, Phin Kon, Sui, Macdougall, Iain, Lioudaki, Eirini, Shah, Sapna, Sharpe, Claire, Aguilar, Francisco, Hernandez Pena, Abegail, Pugay, Conception, Te, Amelia, Finn, Hugh, Hanif, Wasim, Mostafa, Samiul, Aitken, Alice, Draxlbauer, Katharine, Grobovaite, Evelina, Kearney, Jennifer, Mccarthy, Theresa, Gentile, Giorgio, Browne, Duncan, Chellamuthu, Palanichamy, Dugal, Tabinda, Chant, Terri, Jones, Laura, Laity, Emily, Miners, Megan, Muir, Jame, Swanson, Elizabeth, Frankel, Andrew, Tomlinson, Jame, Alegata, Marlon, Almasarwah, Rashid, Apostolidi, Anthoula, Vourvou, Maria, Walters, Thoma, Taal, Maarten, Dukka, Hari, Kolhe, Nitin, Mcdonald, Carly, White, Kelly, Ugni, Shiva, Gunda, Smita, Oluyombo, Rotimi, Brindle, Vicki, Coutts, Ping, Fuller, Tracy, Nadar, Evelyn, Ramadoss, Suresh, Motherwell, Nichola, Pajak, Susannah, Tonks, Louise, Bhandari, Sunil, Bodington, Richard, Hazara, Adil, Fellowes, Dominic, Wong, Christopher, Goldsmith, Christopher, Barnes, Sherald, Bennett, Ann, Burston, Claire, Hope, Samantha, Hunt, Nicola, Kurian, Lini, Fish, Richard, Farrugia, Daniela, Lee, Judy, Sadler, Emma, Turner, Hannah, Hill, Christopher, Brown, Henry, Masengu, Agne, Maxwell, Peter, Bleakley, Nina, Murtagh, Hugh, Petchey, William, Yiu, Vivian, Kellett, Joanne, Williams, Angharad, Clarke, Helen, Carnall, Victoria, Benyon, Sarah, Blake, Caroline, Estcourt, Stephanie, Piper, Jane, Morgan, Neal, Hutchinson, Carolyn, Mckinley, Teresa, Woodman, Alastair, Graham, Judi, Leonard, Niall, Smyth, John, Adell, Vicki, Hagan, Samantha, Caplin, Ben, Oomatia, Amin, Damian, Eleanor, Sobande, Toluleyi, Doulton, Tim, Delaney, Michael, Montasser, Mahmoud, Hansen, Jenny, Loader, David, Moon, Angela, Morris, France, Sinha, Smeeta, Chukwu, Chukwuma, Hudson, Amy, Campbell, Diane, Kershaw, Melanie, Whittaker, Stephanie, Irtiza-Ali, Ayesha, Ghalli, Farid, Nosseir, Heba, Leslie, Allison, Trivedi, Kate, Fraser, Donald, Alhadj Ali, Mohammad, Griffin, Sian, Latif, Farah, Witczak, Justyna, Wonnacott, Alexa, Jeffers, Lynda, Webley, Yvette, Phelan, Paul, Miller-Hodges, Eve, Geddes, Ailsa, Glenwright, Margaret, Hunter, Amy, Pickett, Thoma, Moriarty, Jim, Hill, Linda, Tyler, Amanda, Ayub, Waqar, Evans, Gail, Hewins, Sue, Hewitt, Davina, Read, Kerry, Bell, Samira, Cosgrove, Leanne, Craik, Rachel, Murray, Shona, Bhandary, Nitin, Coles, Holly, Easow, Rashmi, Joseph, Maya, Khwaja, Arif, Jackson, Yvonne, Mbuyisa, Angeline, Sellars, Rachel, Chitalia, Nihil, Mohandas, Cynthia, Gherman, Anca, Kamundi, Charlotte, Olufuwa, Olumide, Mccafferty, Kieran, Adeleke, Adedolapo, Healy, Cara, Jeyarajah, Damini, Kinsella-Perks, Edward, Smith, Richard, Camilleri, Brian, Buckman, Carol, Finch, Jenny, Rivers, Vanessa, Connor, Andrew, Carr, Sheila, Shainberg, Lisa, Lewington, Andrew, Baker, Richard, Dorey, Suzannah, Tobin, Kay, Wheatley, Rosalyn, Banerjee, Debasish, Hull, Richard, Abat, Sharirose, Paul, Riny, Karim, Mahzuz, Htet, Zay, Tufail, Saad, Varma, Ravi, Convery, Karen, Fottrell-Gould, Deirdre, Hudig, Lisa, Tropman, Emily, Abdul-Samad, Thahir, Grace, Anne, Phipps, Marie, Suckling, Rebecca, Somalanka, Subash, Sood, Bhrigu, Swift, Pauline, Acheampong, Sarah, Ansu, Kwame, Augustin, Martia, Sampson, Anna, Vinall, Lynn, Wren, Kim, Wanninayake, Shamila, Wooding, Nichola, Edwards, Heather, Owen, Lydia, Bolton, Stephanie, Carson, Marion, Matthews, Michael, Brunskill, Nigel, Jesus-Silva, Jorge, Howson, Alex, Quashie-Akponeware, Mary, Tindall, Hilary, Nethaji, Chidambaram, Eldon, Helen, Patel, Rajan, Mark, Patrick, Rankin, Alastair, Sullivan, Michael, Forsyth, Kirsty, Mcdougall, Rowan, Dasgupta, Tanaji, Davies, Louisa, Ryder, Maggie, Grimmer, Philip, Macdonald, Clare, Webster, Mary, Newcastle, Newcastle, Ellam, Timothy, Wong, Edwin, Meshykhi, Christine, Webster, Andrea, Wilson, Peter, Vilar, Enric, Berdeprado, Jocelyn, Doctolero, Eunice, Wilkinson, Lily, Mccarroll, Frank, Ammar, Hesham, Kuan, Ying, Moran, Conor, Shivashankar, Girish, Campbell, Ryan, Glowski, Deborah, Mcdermott, Paula, Ali, Amar, Patel, Zuber, Bond, Christine, Whalley, Gillian, Zhang, Haitao, Yang, Liu, Zhang, Lihua, Kan, Tingting, Zhu, Ling, Zhao, Jinghong, Hou, Weiping, Wu, Jing, Cheng, Hong, Bian, Weijing, Zhao, Zhirui, Shao, Fengmin, Cao, Huixia, Jiao, Xiaojing, Niu, Peiyuan, Niu, Jianying, Chen, Yu, Zhang, Lihong, Zhu, Shenglang, Lin, Haiyan, Yao, Shaopeng, Chen, Jiehui, Jiang, Ying, Hu, Ying, Xiao, Huaying, Yang, Fuye, Zhang, Xinzhou, Guo, Baochun, Jin, Qiu, Liu, Lixia, Xiao, Xiangcheng, Xie, Yanyun, Meng, Ting, Xu, Chuanwen, Huang, Jie, Xu, Yanmei, Kong, Weixin, Wang, Xiaoliang, Liu, Qianpan, Wang, Xueying, Gao, Ming, Hu, Xiumei, Lu, Ying, Wang, Li, Peng, Kun, Wang, Wei, Gong, Qiuhong, Cai, Jianfang, Li, Xiaojue, Liu, Xuejiao, Zhou, Shuhan, Liu, Hong, Weng, Yao, Tang, Shuai, Yao, Yao, Zhao, Shi, Cheng, Chen, Wei, Wei, Li, Na, Aqashiah Mazlan, Sadanah, Zubaidah Bahtar, Alia, Katiman, Elliyyin, Othman, Noraini, Mushahar, Lily, Mazlan, Nurdiana, Sharafina Safiee, Nur, Ramasamy, Sarasa, Seng Wong, Hin, Ahmad Rosdi, Hajar, Zhao Zhi Tan, Esther, Fan Tay, Ju, Seng Teng, Kok, Yahaya, Hasnah, Jiun Liu, Wen, Wee Ee, Lik, Kay Leong Khoo, Kenneth, Mohd Yusoff, Yuana, Safhan Mohamad Nor, Fariz, Kamil Ahmad, Mohd, Ramli Seman, Mohd, Hui Hong Tan, Clare, Lui Sian Ngu, Laura, Yoke May Chan, Jaime, Peji, Javelin, Loong Loh, Chek, Yan Lee, Yee, Ramanaidu, Sridhar, Mean Thong, Kah, Hong Wong, Yik, Junus, Suria, Hua Ching, Chen, Faisal Asmee, Mohammad, Ruziana Ku Md Razi, Ku, Leong Low, Chun, Sze Bing Sim, Christopher, Duan Tham, Zhang, Kamila Abdullah, Noor, Meng Chen, Tai, Chieh Chan, Yong, Chang, Eason, Yean Kang, Huan, Quan Lee, Kai, Ann Lee, Sue, Kheng Lee, Aik, Vinathan, Jeevika, Abdul Cader, Rizna, Mustafar, Ruslinda, Kamaruzaman, Lydia, Mohd, Rozita, Ismail, Rahimah, Men Leong, Chong, Koon Low, Chee, Wei Wong, Liang, Adnan, Norlezah, Ibrahim, Sabariah, Zaimi Abdul Wahab, Mohamad, Bavanandan, Sunita, Shen Lim, Yik, Hazlina Wan Mohamad, Wan, Munirah Jaafar, Siti, Ashykeen Mohd Fauzi, Nur, Sudin, Aziee, Kun Lim, Soo, Chung Gan, Chye, Hing, Albert, Ahmad Faizal Alaidin Razali, Wan, Fong Liew, Yew, Bao Tyng Chan, Chelsia, Chih Cheng, Mei, Chen Ong, Yu, Meng Ong, Loke, Amalina Mohamed Affandi, Farah, Rahmat, Korina, Chai Peng, Ban, Amat, Masayu, Hadafi Ahmad, Nuzaimin, Yee Mah, Doo, Loon Tye, Yi, Azhari, Zaid, Nabilah Mohamad Zaini, Siti, Aidil Musa, Mohd, Ahmad Miswan, Norazinizah, Ramli, Rafizanur, Aziah Ahmad, Nor, Leong Goh, Bak, Izah Ahmad, Nurul, Huda Ibrahim, Fairol, Jian Ng, Tze, Shanmuganathan, Malini, Lian Tay, Li, Harun, Zaiha, Ramli, Salmi, 'Ain Yusof, Nurul, Abd Rahman, Rossenizal, Iqbal Abdul Hafidz, Muhammad, Hidayati Mohd Sharif, Nur, Yasmoon Awang, Irda, Nakashima, Eitaro, Imamine, Rui, Minatoguchi, Makiko, Miura, Yukari, Nakaoka, Miduki, Suzuki, Yoshiki, Yoshikawa, Hitomi, Shin, Koki, Fujita, Kanae, Iwasa, Misuzu, Sasajima, Haruka, Sato, Airi, Hamamoto, Yoshiyuki, Fujita, Yuki, Haraguchi, Takuya, Hyo, Takanori, Izumi, Kiyohiro, Komiya, Toshiyuki, Kubota, Sodai, Kurose, Takeshi, Kuwata, Hitoshi, Nakatani, Susumu, Oishi, Kaori, Okamoto, Saki, Okamura, Kaori, Takeoka, Jun, Tanaka, Nagaaki, Tanigaki, Katsuya, Toda, Naohiro, Watanabe, Koin, Komori, Hiromi, Kumuji, Rika, Takesada, Asako, Tanaka, Aya, Maruyama, Shoichi, Hasegawa, Tomonori, Ishiguro, Akiko, Ishimoto, Takuji, Ito, Kazuhiro, Kamimura, Yutaka, Kato, Noritoshi, Kato, Sawako, Kojima, Hiroshi, Kosugi, Tomoki, Maeda, Kayaho, Mizuno, Masasi, Saito, Shoji, Sato, Hitomi, Sato, Yuka, Suzuki, Yasuhiro, Tanaka, Akihito, Yasuda, Yoshinari, Hasegawa, Fujiko, Hayashi, Maiko, Higashi, Shizuka, Shimamura, Kaho, Sumi, Momoko, Tajima, Kazuki, Unekawa, Chimaki, Wakayama, Kana, Wakita, Yukiko, Otani, Takatoshi, Imai, Ayako, Kawashima, Sayaka, Kogure, Eri, Sato, Tomoe, Takezawa, Misato, Yoshida, Shinya, Araki, Hideo, Katsuda, Yuko, Konishi, Masahiro, Matsunaga, Takahiro, Oe, Masashi, Ogane, Kunihiro, Sakai, Masato, Takahashi, Tomoko, Yamano, Takahiro, Yokoyama, Takuya, Ito, Hitomi, Katayama, Masayo, Kuroda, Emi, Ikeda, Toru, Kojo, Takuma, Yoshidome, Etsuo, Mizumachi, Rieko, Yamamoto, Akane, Yamasaki, Narihisa, Yamasaki, Yoshihiko, Wada, Jun, Eguchi, Jun, Higuchi, Chigusa, Katayama, Akihiro, Kinomura, Masaru, Kitagawa, Masashi, Kitamura, Shinji, Miyamoto, Satoshi, Morinaga, Hiroshi, Nakatsuka, Atsuko, Nojima, Ichiro, Shikata, Kenichi, Sugiyama, Hitoshi, Tanabe, Katsuyuki, Tsuji, Kenji, Uchida, Haruhito, Watanabe, Mayu, Hashimoto, Chie, Kato, Takahiro, Yamamoto, Sayaka, Wada, Takehiko, Fukagawa, Masafumi, Hamano, Naoto, Koizumi, Masahiro, Komaba, Hirotaka, Nakagawa, Yosuke, Iwamoto, Michiyo, Masutani, Kosuke, Katanosaka, Akane, Kiyota, Mayu, Uchi, Hikari, Ueda, Yuka, Yamamoto, Sonoka, Nagasu, Hajime, Itano, Seiji, Iwakura, Tsukasa, Kadoya, Hiroyuki, Kanda, Eiichiro, Kashihara, Naoki, Kidokoro, Kengo, Kondo, Megumi, Sasaki, Tamaki, Satoh, Minoru, Tokuyama, Atsuyuki, Umeno, Reina, Wada, Yoshihisa, Yamamoto, Toshiya, Yamanouchi, Yu, Abe, Masumi, Inukai, Yoko, Ogawa, Wataru, Asahara, Shunichiro, Fujii, Hideki, Goto, Shunsuke, Hirota, Yushi, Hosooka, Tetsuya, Kono, Keiji, Nishi, Shinichi, Okada, Yuko, Sakaguchi, Kazuhiko, Sugawara, Kenji, Takahashi, Michiko, Takai, Tomoko, Tamori, Yoshikazu, Watanabe, Kentaro, Kitajima, Miyu, Nishi, Misaki, Wada, Junko, Ito, Yasuhiko, Kamiya, Hideki, Asai, Akimasa, Asai, Nao, Asano, Saeko, Banno, Shogo, Ejima, Yohei, Hase, Hanako, Hayami, Tomohide, Himeno, Tatsuhito, Ishikawa, Takahiro, Ito, Mayumi, Iwagaitsu, Shiho, Kasagi, Rina, Kato, Yoshiro, Kato, Makoto, Kato, Koichi, Katsuno, Takayuki, Kawai, Miyuka, Kinashi, Hiroshi, Kondo, Masaki, Koshino, Masako, Matsuoka, Naoya, Morishita, Yoshiaki, Motegi, Mikio, Nakamura, Jiro, Shimoda, Hiromi, Sugiyama, Hirokazu, Tsunekawa, Shin, Yamaguchi, Makoto, Takahashi, Kazuyo, Watada, Hirotaka, Funayama, Takashi, Furukawa, Yasuhiko, Gohda, Tomohito, Goto, Hiromasa, Kaga, Hideyoshi, Kanaguchi, Yasuhiko, Kanazawa, Akio, Kaneko, Kayo, Kano, Toshiki, Kihara, Masao, Kimura, Shogo, Kobayashi, Takashi, Maiguma, Masayuki, Makita, Yuko, Mano, Satoshi, Mita, Tomoya, Miyatsuka, Takeshi, Murakoshi, Maki, Muto, Masahiro, Nakata, Masami, Nakata, Junichiro, Nishida, Yuya, Nohara, Nao, Ogihara, Takeshi, Sato, Daisuke, Sato, Junko, Sato, Hiroaki, Suzuki, Yusuke, Suzuki, Ruka, Suzuki, Hitoshi, Takagi, Miyuki, Tamura, Yoshifumi, Uchida, Toyoyoshi, Ueda, Seiji, Asawa, Miki, Miyaji, Minako, Nagashima, Eri, Shibata, Yoshie, Yanagisawa, Eri, Yamauchi, Toshimasa, Hirakawa, Yosuke, Nishi, Hiroshi, Shojima, Nobuhiro, Horikawa, Satoko, Nakayama, Yukiko, Yamada, Naoko, Omori, Yuki, Yano, Shintaro, Ioka, Miyabi, Kuwabara, Nahoko, Nagano, Remi, Nozawa, Megumi, Osawa, Yumi, Maegawa, Hiroshi, Kume, Shinji, Araki, Shinichi, Miyazawa, Itsuko, Morino, Katsutaro, Kawai, Ikuko, Sobata, Masumi, Takaoka, Motoko, Iwaita, Yasushi, Udagawa, Takashi, Inamori, Ami, Kawase, Aya, Yamanaka, Aya, Shimano, Hitoshi, Fujita, Akiko, Iwasaki, Hitoshi, Kai, Hirayasu, Osaki, Yoshinori, Saito, Chie, Sekiya, Motohiro, Tsunoda, Ryoya, Yamagata, Kunihiro, Nakamura, Rikako, Yamada, Aiko, Ohsugi, Mitsuru, Awazawa, Motoharu, Bouchi, Ryotaro, Hashimoto, Shota, Hashimoto, Makiko, Hisatake, Tomoko, Ihana, Noriko, Ishizuka, Koko, Izumi, Kazuo, Kajio, Hiroshi, Kobayashi, Michi, Kodani, Noriko, Maruyama, Koji, Matsumoto, Michihiro, Matsushita, Maya, Nakamura, Tomoka, Sugiyama, Takehiro, Tanabe, Akiyo, Terakawa, Aiko, Ueki, Kojiro, Orimo, Yuko, Ozawa, Takako, Takahira, Eriko, Yamasaki, Yoshimitsu, Haneda, Masakazu, Tomita, Tadahiro, Akimoto, Saori, Fujimoto, Akihiro, Ishihara, Kenji, Murakami, Chiho, Nishiyama, Akiyo, Toyonaga, Yukiko, Uozumi, Kana, Yamaji, Yukihiro, Shigehara, Tetsuya, Okajyo, Jun, Shimizu, Yukihiro, Iwasaki, Shingo, Fukao, Yuki, Furusho, Megumi, Nunokawa, Shintaro, Katagiri, Hideki, Izumi, Tomohito, Kaneko, Keizo, Kodama, Shinjiro, Miyazaki, Mariko, Munakata, Yuichiro, Nagasawa, Tasuku, Oe, Yuji, Sugawara, Hiroto, Takahashi, Kei, Hirata, Kazushige, Inomata, Keiko, Otomo, Shoko, Uchida, Taeko, Yamashita, Chigusa, Kiyosue, Arihiro, Tamura, Ryota, Dube, Francoi, Bolduc, Marilene, Talbot, Marie-Christine, Cham, Leslie, Lai, Vesta, Tse, Josephine, Jolly, Shivinder, Duck, Tabbatha, Lyle, Scott, Epp, Rachel, Galloway, Camille, Haskett, Susan, Matvienko, Elizabeta, Paulsen, Liam, Moist, Louise, Lozon, Zabrina, Ramsey, Tina, Whitmore, Brittany, Al-Zeer, Bader, Macleod, Paula, O'Sullivan, Aoife, Sheriff, Zainab, Tholl, Sam, Pandey, Amritanshu, Armstrong, Samantha, Gebeyehu, Bethelihem, Toth, Patrick, Goldenberg, Ronald, Jahangiriesmaili, Mahsa, Sanguila, Shariff, Suresh, Neethi, Talsania, Tanvi, Zalunardo, Nadia, Agharazii, Mohsen, Roussel, Marie-Pier, Saillant, Annie, Samson, France, Bajaj, Harpreet, Bhavsar, Miken, Dhall, Parul, Dhillon, Gagandeep, Grewal, Bhupinder, Nimbkar, Taniya, Madore, Francoi, Marcotte, Guylaine, Steen, Oren, Bullen, Mathura, Raguwaran, Shayani, Valleteau, Andre, Langlois, Marie-France, Brown, Christine, Steele, Andrew, Garrity, Melissa, Ghate, Taneera, Robinson, Holly, Tolibas, Michael, Tailor, Chetna, Elliott, Lauren, McClary-Wright, Christine, Boreky, Fadia, Fikry, Sameh, Ali, Ayesha, Barot, Chintankumar, Basily, Wagdy, Saram, Thisun, Varad, Vinay, Khandwala, Hasnain, Aguilera, Alex, Alvarez, Patricia, Gill, Balwinder, Huda, Nazihah, Navivala, Aamir, Pinto, Daniel, Bevilacqua, Micheli, Fung, Elaine, Hernandez, Geraldine, Mann, Puneet, Saini, Jaskiran, Rabasa-Lhoret, Remi, Bovan, Danijela, Devaux, Marie, Barnini, Cecilia, Leoncini, Giovanna, Manco, Luca, Nobili, Giulia, Piemontese, Matteo, Aucella, Filippo, Grifa, Rachele, Totaro, Francesco, La Manna, Gaetano, Capelli, Irene, Cianciolo, Giuseppe, Lerario, Sarah, Zappulo, Fulvia, Rosati, Alberto, Fani, Filippo, Spatoliatore, Giuseppe, Gesualdo, Loreto, Pesce, Francesco, Russo, Maria, Zippo, Maria, Cafiero, Cesira, Motta, Daria, Bianco, Simona, Bilucaglia, Donatella, Messa, Piergiorgio, Pavone, Laura, Tripodi, Federica, Vettoretti, Simone, Fioretto, Paola, Carraro, Gianni, Farnia, Filippo, Postal, Anna, D'Amelio, Alessandro, Cardone, Antonio, Piccinni, Giovanni, Aloisi, Annalisa, Scolari, Francesco, Alberici, Federico, Guerini, Alice, Saccà, Chiara, Salviani, Chiara, Zani, Roberta, DE NICOLA, Luca, Garofalo, Carlo, Elena Liberti, Maria, Minutolo, Roberto, Pennino, Luigi, Polese, Lucio, Mené, Paolo, Barberi, Simona, Falcone, Clorinda, Russo, Francesco, Caroppo, Maurizio, Santorelli, Gennaro, Rivera, Rodolfo, Santoro, Domenico, Giuffrida, Alfio, Zirino, Fortunata, Calvi, Cristina, Estienne, Luca, Gambaro, Giovanni, Gangemi, Concetta, Ortalda, Vittorio, Pessolano, Giuseppina, Grandaliano, Giuseppe, Baccaro, Rocco, Ferraro, Pietro, Mangiacapra, Roberto, Melandri, Marco, Foligno, Nadia, Quartagno, Rita, Vezzoli, Giuseppe, Brioni, Elena, and Group, EMPA-KIDNEY Collaborative
Subjects: chronic renal disease, empagliflozin, empa-kidney, General Medicine
Abstract: Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; PConclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110. opens in new tab; EudraCT number, 2017-002971-24. opens in new tab.)
Published: 2023

38. Glycemic control using intermittently scanned continuous glucose monitoring in patients with diabetes requiring methylprednisolone therapy for severe COVID-19

Author: Masaki Uchihara, Noriko Kodani, Ryotaro Bouchi, Sho Saito, Yusuke Miyazato, Hirofumi Sugimoto, Kotaro Umamoto, Michi Kobayashi, Noriko Ihana-Sugiyama, Mitsuru Ohsugi, Akiyo Tanabe, Kohjiro Ueki, Jin Takasaki, Masayuki Hojo, and Hiroshi Kajio
Subjects: Perspective, General Medicine
Abstract: In patients with severe coronavirus disease 2019 (COVID-19) with diabetes, glycemic control is essential for a better outcome, however, we face difficulty controlling hyperglycemia induced by high-dose glucocorticoids. We report five cases of severe COVID-19 patients with diabetes, whose glycemic control was managed using an intermittently scanned continuous glucose monitoring (isCGM) system during methylprednisolone therapy. Patients using isCGM showed significantly lower average blood glucose levels and significantly higher total daily insulin dose during the methylprednisolone therapy, compared to patients under regular blood glucose monitoring. The use of isCGM enables remote glucose monitoring, and this can reduce the risks of healthcare workers who have frequent contact with the patients. Thus, we suggest that using isCGM should be considered in hospitalized patients with diabetes under the COVID-19 pandemic to achieve better glycemic control and to minimize the possible risks of healthcare workers.
Published: 2022

39. Lack of Awareness of Own Hypercholesterolemia or Statin Medication among Adult Statin Users in the United States: Prevalence and Patient Characteristics in a Repeated Cross-Sectional Study

Author: Kenjiro Imai, Takehiro Sugiyama, Mitsuru Ohsugi, Masafumi Kakei, and Kazuo Hara
Subjects: Adult, Male, Health, Toxicology and Mutagenesis, Hypercholesterolemia, Public Health, Environmental and Occupational Health, nutritional and metabolic diseases, Hyperlipidemias, Nutrition Surveys, United States, Cross-Sectional Studies, hypercholesterolemia, statin, prescription medication, lack of awareness, Cardiovascular Diseases, Diabetes Mellitus, Prevalence, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Aged
Abstract: Knowledge of a patient’s medication is important in treating hyperlipidemia; however, little is known about this in practice. We carried out a repeated cross-sectional study to analyze a nationally representative sample of US adult statin users from the National Health and Nutrition Examination Survey, 1999–2018. We used medication bottle checks and self-reported survey data to estimate the percentage of individuals who are unaware of their hypercholesterolemia, type of medication, or how to take their medication. We used logistic regression to examine their characteristics. We included 8798 statin users; however, 17.6% were unaware of their hypercholesterolemia or statin use. Being older, male, non-Hispanic Black, taking a wider range of prescription medications, and previous diabetes or cardiovascular disease diagnosis were associated with lack of awareness. Serum low-density lipoprotein cholesterol level was lower among those lacking awareness (85.5 vs. 100.7 mg/dL; p < 0.001). Many of those unaware of drug type had been given little information about statins; 34.0% had no diagnosis of diabetes or cardiovascular disease, and of these, 27.1% were >75 years old. Roughly one in six lacked awareness, but no association was found with hypercholesterolemia control. Healthcare providers should ascertain a patient’s understanding and consider the risks and benefits of statin medication.
Published: 2022

40. Patient Satisfaction and Clinical Efficacy of Flash Glucose Monitoring in Patients with Type 1 Diabetes: A Prospective, Single-Center, Single-Arm Study

Author: Daisuke Chujo, Hiroshi Kajio, Keisuke Ueno, Nobuyuki Takahashi, Mitsuru Ohsugi, and Kohjiro Ueki
Subjects: Quality of life, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Satisfaction, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Single Center, 03 medical and health sciences, chemistry.chemical_compound, Flash glucose monitoring, 0302 clinical medicine, Patient satisfaction, Interquartile range, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Type 1 diabetes, business.industry, Brief Report, medicine.disease, Clinical trial, chemistry, Glycated hemoglobin, business
Abstract: Introduction Frequent self-monitoring of blood glucose (SMBG) is usually required in patients with type 1 diabetes (T1D). However, the fear of self-testing, hygiene, and social obstacles may deter some patients from SMBG. Flash glucose monitoring (FGM), a less-invasive glucose monitoring method, was launched in Japan in September 2017. The aim of this study was to evaluate patient satisfaction and the clinical efficacy of FGM in Japanese patients with T1D. Methods Patient satisfaction with FGM was assessed using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and Diabetes Therapy-Related Quality of Life (DTR-QOL) questionnaire before (baseline) and 4 and 12 weeks after initiating FGM use in 20 Japanese patients with T1D. Clinical parameters related to glucose metabolism, such as glycated hemoglobin (HbA1c) levels, were assessed, and glucose fluctuations were evaluated using the FGM data. Values at 4 and 12 weeks after initiating FGM were compared with baseline data using the Wilcoxon signed-rank test. The mean absolute relative difference (MARD) between glucose values detected using the FGM device and by SMBG was also calculated. Results The DTSQ scores significantly improved 12 weeks after initiating FGM (P
Published: 2020

41. A global approach to identify differentially expressed genes in cDNA (two-color) microarray experiments.

Author: Yiyong Zhou, Corentin Cras-Méneur, Mitsuru Ohsugi, Gary D. Stormo, and M. Alan Permutt
Published: 2007
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42. Factors associated with the degree of glycemic deterioration among patients with type 2 diabetes who dropped out of diabetes care: A longitudinal analysis using medical claims and health checkup data in Japan

Author: Hirokazu Tanaka, Takehiro Sugiyama, Ayako Yanagisawa-Sugita, Nanako Tamiya, Kohjiro Ueki, Kenjiro Imai, Yasuki Kobayashi, Mitsuru Ohsugi, and Noriko Ihana-Sugiyama
Subjects: Adult, Blood Glucose, Male, Pediatrics, medicine.medical_specialty, medicine.drug_class, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Dropout (communications), Type 2 diabetes, Japan, Diabetes mellitus, Internal Medicine, medicine, Humans, Hypoglycemic Agents, Glycemic, Retrospective Studies, Glycated Hemoglobin, business.industry, Insulin, nutritional and metabolic diseases, Retrospective cohort study, General Medicine, Middle Aged, medicine.disease, Sulfonylurea, INSULIN USE, Diabetes Mellitus, Type 2, business
Abstract: AIMS/INTRODUCTION To identify factors associated with worsening glycemic control after discontinuing diabetes care among patients with type 2 diabetes. MATERIALS AND METHODS This retrospective cohort study combined medical claims and health checkup data between January 2005 and April 2018. Adult Japanese workers with type 2 diabetes who had dropped out from diabetes care for ≥4 months after receiving ≥18 months of non-intermittent care and had health checkup information both before and after the dropout were included. Factors associated with changes in HbA1c during the dropout period were identified using multiple linear regression analyses and depicting restricted cubic spline (RCS) curves. RESULTS A total of 1,125 patients (mean age: 51.2 years, baseline HbA1c: 6.8%, and number of males: 93.7%) whose follow-up HbA1c increased to 7.6% after a mean 9.3-month dropout period were included. Deterioration in HbA1c was associated with higher baseline HbA1c and sulfonylurea or insulin use. The RCS curves illustrated that patients without antidiabetic medication had small changes in HbA1c (+0.5% from a baseline HbA1c of 7.0%), whereas those using sulfonylureas or insulin had an approximately 2% or more increase in HbA1c even when maintaining reasonable glycemic control before dropping out. CONCLUSIONS Overall in this study, glycemic control worsened during treatment interruptions among patients who were mainly male employees. However, changes in HbA1c greatly varied based on baseline HbA1c and antidiabetic medication type. Caring for patients at risk of worsening glycemic control due to treatment dropout, especially those using sulfonylurea and insulin, is imperative.
Published: 2021

43. Evaluation of cellular and humoral autoimmunity before the development of type 1 diabetes in a patient with idiopathic CD4 lymphocytopenia

Author: Akitsu Kawabe, Daisuke Chujo, Hiroshi Kajio, Kohjiro Ueki, Koji Maruyama, Mitsuru Ohsugi, Koji Watanabe, Takehiro Sugiyama, and Akiyo Tanabe
Subjects: 0301 basic medicine, medicine.medical_specialty, Idiopathic CD4 lymphocytopenia, Endocrinology, Diabetes and Metabolism, Case Report, 030204 cardiovascular system & hematology, medicine.disease_cause, Gastroenterology, Diseases of the endocrine glands. Clinical endocrinology, Autoimmunity, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Type 1 diabetes, Seroconversion, T cells, biology, business.industry, General Medicine, Articles, medicine.disease, RC648-665, 030104 developmental biology, Clinical Science and Care, Etiology, biology.protein, Lymphocytopenia, Antibody, business, CD8
Abstract: A 64‐year‐old woman developed type 1 diabetes 23 years after the diagnosis of idiopathic CD4 lymphocytopenia. To investigate the etiological interaction between idiopathic CD4 lymphocytopenia and type 1 diabetes, we carried out a longitudinal analysis related to islet‐specific autoimmunity. Anti‐glutamic acid decarboxylase antibody had been already weakly positive for at least 16 years and started rising at 6 months before the onset of type 1 diabetes. The seroconversion of anti‐insulinoma‐associated antigen‐2 antibody and insulin autoantibody occurred at the time of onset. The ratio of CD8/CD4 had been gradually increasing for 8 years before type 1 diabetes onset. Notably, islet‐specific glucose‐6‐phosphatase catalytic subunit‐related protein‐reactive CD8+ T cells were detected at type 1 diabetes onset, and the frequency was higher than that in 15 non‐diabetic controls (6.75% vs 0.49 ± 0.78%, mean ± SD). The present type 1 diabetes patient, presented with idiopathic CD4 lymphocytopenia and showed an elevated number of CD8+ T cells, including the islet antigen‐specific CD8+ T cells that might contribute to autoimmune destruction of pancreatic β‐cells.
Published: 2019

44. Comparison of effectiveness and drug cost between dipeptidyl peptidase‐4 inhibitor and biguanide as the first‐line anti‐hyperglycaemic medication among Japanese working generation with type 2 diabetes

Author: Takehiro Sugiyama, Mitsuru Ohsugi, Hirokazu Tanaka, Noriko Ihana-Sugiyama, Kohjiro Ueki, and Yasuki Kobayashi
Subjects: Adult, Male, medicine.medical_specialty, medicine.drug_class, Type 2 diabetes, Dipeptidyl peptidase-4 inhibitor, Drug Costs, 03 medical and health sciences, Japan, Internal medicine, medicine, Humans, Hypoglycemic Agents, Medical prescription, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Original Paper, Dipeptidyl-Peptidase IV Inhibitors, Biguanide, business.industry, 030503 health policy & services, Health Policy, Drug cost, Public Health, Environmental and Occupational Health, nutritional and metabolic diseases, Middle Aged, medicine.disease, Original Papers, Metformin, Anti hyperglycaemic, Diabetes Mellitus, Type 2, Propensity score matching, type 2 diabetes, 0305 other medical science, business, dipeptidyl peptidase‐4 inhibitor, medicine.drug
Abstract: Aims and Objectives Dipeptidyl peptidase‐4 inhibitor (DPP4i) is widely used for the treatment of type 2 diabetes (T2DM) in several countries such as Japan, whereas biguanide (BG; mostly metformin) is recommended as a first‐line antidiabetic medication in many countries according to evidence mainly from Western countries. Although previous studies reported that DPP4i may be more efficacious for East Asians, direct comparisons of effectiveness and cost between DPP4i and BG have never been conducted in East Asia. Methods We extracted claims and medical check‐up data (observation period from January 2010 to March 2016) of adult patients under 70 years old with T2DM who received DPP4i or BG as first‐line antidiabetic drugs. Changes in HbA1c and BMI before and 2 years after the first prescription and annual cost of antidiabetic medication during the second year were compared between the DPP4i and BG groups. Results We extracted 1034 patients who received DPP4i and 365 patients who received BG as the first antidiabetic medication (male sex, 83.0% and 84.9%; HbA1c (mean [SD]), 7.7 [1.4]% and 7.9 [1.4]%; BMI, 26.6 [4.5] kg/m2 and 28.1 [4.3] kg/m2). After propensity score matching, changes in HbA1c and BMI were not significantly different between the groups (HbA1c, −0.67% vs −0.80% [P = .28]; BMI, −0.3 kg/m2 vs −0.4 kg/m2 [P = .42]). Annual cost of antidiabetic drugs was significantly higher in the DPP4i group (US $458.7 vs 273.3 [P
Published: 2019
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45. 1086-P: A Retrospective Nationwide Surveillance on the First-Line Antidiabetic Medication for the Patients with Type 2 Diabetes in Japan

Author: Kenjiro Imai, Takehiro Sugiyama, Toshimasa Yamauchi, Ryotaro Bouchi, Atsushi Goto, Mitsuru Ohsugi, Noriko Ihana-Sugiyama, Kohjiro Ueki, and Takashi Kadowaki
Subjects: Endocrinology, Diabetes and Metabolism, Life insurance, First line, Internal Medicine, Health insurance, National database, Business, Medical costs, Antidiabetic agents, Management
Abstract: Background: To investigate the national trend in prescription of first-line non-insulin antidiabetic agents and the annual total medical costs since the first prescription in Japanese patients with type 2 diabetes. Materials and Methods: Using the National Database of Health Insurance Claims and Specific Health Check-ups of Japan (NDB), we calculated the proportion of each antidiabetic drug from fiscal year (FY) 2014 to 2017 and determined factors associated with drug selection in multivariable logistic regression analyses. The total medical costs (TMCs) in the first year after starting the drugs were calculated and factors associated with the costs were also determined. Results: Among 1,136,723 newly-prescribed patients, dipeptidyl peptidase-4 inhibitors (DPP4i) were most prescribed (65.1%) followed by biguanides (15.9%) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) (7.6%). SGLT2i use increased markedly, as was biguanide gradually increased and other drug use decreased during the study period. Biguanides were not prescribed at all in 38.2% of non-certified facilities by the Japan Diabetes Society. TMCs [adjusted mean, 95% CI] were lowest in biguanides [$4638, 4591-4686] followed by thiazolidinediones [$4670, 4546-4794], moderate in SGLT2i [$5383, 5297-5468] and DPP4i [$5583, 5550-5617], highest in glucagon-like peptide 1 receptor agonist [$8596, 7532-9661] after adjusting for covariates including age and comorbidities. FY, age, gender, type of insurance, facility, number of beds, and comorbidities were associated with drug choice and medical costs in the model. There was wide regional variation in initial choice of antidiabetic drugs but not in the TMCs. Conclusions: Unlike in Europe and the US, DPP4i stands as a first-line treatment in Japan. The wide variation in the drug choice by facility and prefecture may suggest the need to create a new strategy such as algorithms that facilitate appropriate drug selection in Japan. Disclosure R. Bouchi: None. T. Sugiyama: None. A. Goto: None. K. Imai: None. N. Ihana-sugiyama: None. M. Ohsugi: Other Relationship; Self; Kyowa Kirin Co., Ltd., Research Support; Self; Abbott Japan Co., Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Novartis Pharma K. K., Novo Nordisk Pharma Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd. T. Yamauchi: Other Relationship; Self; Abbott Japan LLC, Astellas Pharma Inc., AstraZeneca K. K., Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyorin Pharmaceutical Company, Limited, Kyowa Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Research Support; Self; Aero Switch, Asahi Mutual Life Insurance Company, Bayer Yakuhin, Ltd., Mitsubishi Corporation Life Sciences Limited, NIPRO Medical Corporation, NTT Docomo Inc., Shionogi & Co., Ltd., Tosoh Corporation. T. Kadowaki: Other Relationship; Self; Asahi Mutual Life Insurance Company, MSD Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd. K. Ueki: Advisory Panel; Self; Abbott Japan Co., Ltd., AstraZeneca K. K., Bayer Yakuhin, Ltd., Novo Nordisk Pharma Ltd., Poxel SA, Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca K. K., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Health and Labour Sciences Research Grants (20FA1016)
Published: 2021
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46. Maturity-Onset diabetes of the young type 5 treated with the glucagon-like peptide-1 receptor agonist: A case report

Author: Aiko Terakawa, Hiroshi Kajio, Shoko Hamano, Kohjiro Ueki, Daisuke Chujo, Akiyo Tanabe, Mitsuru Ohsugi, Kazuki Yasuda, Keisuke Ueno, and Tomoka Nakamura
Subjects: medicine.medical_specialty, Adolescent, MODY 5, glucagon-like peptide-1 receptor agonist, Gastroenterology, Maturity onset diabetes of the young, Glucagon-Like Peptide-1 Receptor, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Central Nervous System Diseases, Diabetes mellitus, Internal medicine, medicine, Humans, Hypoglycemic Agents, 030212 general & internal medicine, Clinical Case Report, Dental Enamel, Pancreas, Glucagon-like peptide 1 receptor, Type 1 diabetes, liraglutide, diabetes, Insulin glargine, Liraglutide, business.industry, General Medicine, Kidney Diseases, Cystic, medicine.disease, chemistry, Diabetes Mellitus, Type 2, maturity-onset diabetes of the young type 5, 030220 oncology & carcinogenesis, Female, Glycated hemoglobin, business, medicine.drug, Research Article
Abstract: Rationale: Maturity-onset diabetes of the young type 5 (MODY 5) is a form of monogenic diabetes that is often accompanied by pancreatic dysfunction. To date, no cases of MODY 5 treated with glucagon-like peptide-1 receptor agonist (GLP-1RA) have been reported. We present the first case of MODY 5 treated with GLP-1RA. Patient concerns: A 17-year-old woman, with a history of being operated for congenital ileal atresia at birth, was admitted to our hospital due to hyperglycemia. She had been clinically diagnosed with type 1 diabetes 1 month prior, and administered 14 units of insulin glargine 300 U/mL per day. Diagnosis: She had hypopotassemia, hypomagnesaemia, pancreatic body, and tail defects, multiple renal cysts, and a family history of diabetes, and urogenital anomaly. Genetic testing revealed heterozygous deletion of hepatocyte nuclear transcription factor-1 beta, leading to the diagnosis of MODY 5. Interventions: The patient was treated with multiple daily insulin injections for 9 days (22 units/d) before administration of GLP-1RA, and then liraglutide was initiated. Outcomes: Liraglutide treatment (0.6 mg/d) alone maintained the patient's glycated hemoglobin level below 7.0% for at least 12 months after discharge. A higher dose, 0.9 mg/d, of liraglutide was not tolerated by the patient due to nausea. Serum levels of C-peptide immunoreactivity were 1.15 ng/mL and 1.91 ng/mL, respectively, after 6 and 12 months of liraglutide therapy. Lessons: GLP-1RA might be effective at regulating glucose metabolism by utilizing residual pancreatic endocrine function in patients with MODY 5. Imaging and genetic screening were helpful in the diagnosis of MODY 5.
Published: 2020

47. Comorbidities and complications in Japanese patients with type 2 diabetes mellitus: Retrospective analyses of J-DREAMS, an advanced electronic medical records database

Author: Jumpei Tetsuka, Jun-ichi Eiki, Kohjiro Ueki, Shigeru Tokita, Mitsuru Ohsugi, and Kristy Iglay
Subjects: Male, Endocrinology, Diabetes and Metabolism, Comorbidity, Overweight, computer.software_genre, Endocrinology, Japan, Diabetes mellitus, Prevalence, Internal Medicine, medicine, Electronic Health Records, Humans, Retrospective Studies, Database, business.industry, Medical record, Type 2 Diabetes Mellitus, General Medicine, medicine.disease, Diabetes Mellitus, Type 2, Child, Preschool, Female, medicine.symptom, business, Complication, computer, Dyslipidemia, Retinopathy, Kidney disease
Abstract: Aims To investigate the prevalence of comorbid conditions/complications among Japanese patients with type 2 diabetes mellitus (T2DM) in a real-world setting. Methods We performed retrospective analyses of a large-scale database directly linked to electronic medical records, J-DREAMS (Japan Diabetes compREhensive database project based on an Advanced electronic Medical record System), to determine the prevalence of clinically significant comorbid conditions/complications among Japanese patients with T2DM aged ≥ 20 years with ≥ 1 clinical encounter at a referral center between April 1, 2017 and March 31, 2019. Results Data were available for 10,151 patients (39.2% female). The mean age and T2DM duration were 66.0 years and 16.1 years, respectively. Only 0.5% had isolated T2DM, 6.6% had one comorbid condition/complication, and the remainder had multiple comorbid conditions/complications. Dyslipidemia (84.7%) and hypertension (75.1%) were the most common, followed by chronic kidney disease (35.4%), retinopathy (23.1%), and cardiovascular diseases (22.1%). Overall, 36.0% of patients were overweight/obese (body mass index ≥ 25 kg/m2) and 18.6% had a history of neoplasms. The prevalence of comorbid conditions/complications tended to increase with advancing age and duration of T2DM. Conclusions We revealed a high prevalence of comorbid conditions/complications, including chronic kidney and cardiovascular diseases, in Japanese patients with T2DM.
Published: 2021
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48. Efficacy and safety of sitagliptin as compared with glimepiride in Japanese patients with type 2 diabetes mellitus aged ≥ 60 years (START-J trial)

Author: Daisuke Yabe, Hitoshi Ishida, Yutaka Seino, Masafumi Kitaoka, Mitsuru Ohsugi, Nobuyuki Shihara, Yasuo Terauchi, Yuichiro Yamada, and Jo Satoh
Subjects: Aging, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Pharmacology, Severity of Illness Index, 0302 clinical medicine, Endocrinology, Japan, Activities of Daily Living, randomized trial, Clinical endpoint, 030212 general & internal medicine, Glycated haemoglobin, Aged, 80 and over, Incidence, Brief Report, clinical trial, DPP‐4 inhibitor, Middle Aged, sulphonylureas, Sitagliptin, medicine.drug, medicine.medical_specialty, 030209 endocrinology & metabolism, Equivalence Trials as Topic, Incretins, sitagliptin, 03 medical and health sciences, Internal medicine, Weight Loss, Internal Medicine, medicine, Humans, Hypoglycemic Agents, Adverse effect, Aged, Glycated Hemoglobin, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Blood Glucose Self-Monitoring, Sitagliptin Phosphate, Reproducibility of Results, nutritional and metabolic diseases, Type 2 Diabetes Mellitus, Hypoglycemia, Confidence interval, Glimepiride, Sulfonylurea Compounds, Diabetes Mellitus, Type 2, Hyperglycemia, Brief Reports, Once daily, business
Abstract: The aim of this study was to evaluate the efficacy and safety of sitagliptin administered to elderly patients with type 2 diabetes mellitus (T2DM) for 1 year as compared with glimepiride. Patients aged ≥60 years with T2DM and inadequately controlled blood glucose were randomly assigned to sitagliptin 50 mg once daily or glimepiride 0.5 mg once daily for 52 weeks. The primary efficacy endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 52. Secondary efficacy endpoints included self‐monitored blood glucose and weight. Safety endpoints were adverse events including hypoglycaemia. Administration of sitagliptin or glimepiride to elderly patients with T2DM resulted in a significant decrease in HbA1c change from baseline. At 52 weeks, the least squares mean difference between the treatments was 0.11% (95% confidence interval [CI] −0.02 to 0.24; P = .087) (1.2 mmol/mol [−0.2 to 2.6]). The upper limit of the CI was below the predefined non‐inferiority margin (0.3% [3.3 mmol/mol]), demonstrating non‐inferiority of sitagliptin to glimepiride for the primary endpoint. Sitagliptin resulted in a significantly lower incidence rate of non‐serious hypoglycaemia than glimepiride during the 52 weeks (4.7% vs 16.1%; P = .002); thus, sitagliptin is a useful therapeutic option for elderly patients with T2DM.
Published: 2017
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49. Left Hemiplegia Possibly Due to Glucose Reperfusion Injury after Recovery of Severe Hypoglycemia in a Woman with Type 2 Diabetes Mellitus.

Author: Erika Sugito, Tetsuro Tsujimoto, Noritoshi Arai, Ryotaro Bouchi, Mitsuru Ohsugi, Akiyo Tanabe, Kohjiro Ueki, and Hiroshi Kajio
Published: 2022
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50. Effects of storage temperature, storage time, and Cary-Blair transport medium on the stability of the gut microbiota

Author: Mitsuru Ohsugi, Tomoka Nakamura, Kohjiro Ueki, Mari Tohya, Wataru Suda, Naomi Uemura, Fumihiko Takeuchi, Masahira Hattori, Tetsuro Tsujimoto, Tohru Miyoshi-Akiyama, Takashi Kawai, Naoyoshi Nagata, and Suguru Nishijima
Subjects: Preservative, Time Factors, Gut flora, Actinobacteria, Specimen Handling, 03 medical and health sciences, Feces, RNA, Ribosomal, 16S, Humans, Pharmacology (medical), Microbiome, Food science, General Pharmacology, Toxicology and Pharmaceutics, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, Chemistry, Temperature, Bacteroidetes, General Medicine, Isolation (microbiology), biology.organism_classification, Culture Media, Gastrointestinal Microbiome, Survival Rate, Anaerobic exercise
Abstract: How long fecal samples can withstand a period of refrigeration or room temperature, and the appropriate preservative, are largely unknown. Cary-Blair transport medium has been used for many years because it is inexpensive and prevents bacterial overgrowth. However, its effectiveness for metagenomic analyses has never been tested. We found that the microbial compositions using a 16S rRNA sequence of samples left at 4°C for 3 or 7 days or at 25°C for 1, 3, or 7 days differed significantly from samples stored at -80°C in no-preservative method. Whereas samples stored in Cary-Blair medium remained unchanged for longer periods. The relative abundances of phylum Bacteroidetes and Actinobacteria, changed significantly at 25°C, whereas Cary-Blair medium inhibited the reduction in Bacteroidetes and the increase in Actinobacteria. The bacterial survival counts were significantly lower in the RNAlater samples than in the Cary-Blair samples under aerobic and anaerobic culture conditions. In conclusion, storage time and storage temperature significantly affect the gut microbial composition in fecal samples. Given the low cost, inhibitory effect on bacterial changes, and potential utility in bacterial isolation, Cary-Blair medium containers are suitable for large-scale or hospital-based microbiome studies, especially if direct freezing at -80°C is unavailable.
Published: 2019

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