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OBJECTIVE The goal of this study was to clarify the clinical utility of paravertebral foramen screws (PVFSs) and to determine intraoperative indicators for appropriate screw placement during posterior cervical fusion surgery to improve its safety. METHODS The authors included data from 46 patients (29 men and 17 women, mean age 61.7 years) who underwent posterior cervical spine surgery with 94 PVFSs. Of the 94 PVFSs, 77 were used in C6, 9 in C3, 5 in C4, and 3 in C5. According to the cervical lateral radiographic view, the authors divided the 94 PVFSs into 3 groups as follows: a longer group, in which the tip of PVFS was located anteriorly from the line of the posterior wall of the vertebral body (> +0 mm); an intermediate group, in which the screw tip was located up to 2 mm posteriorly to the posterior wall of the vertebral body (–2 to 0 mm); and a shorter group, in which the screw tip was located more than 2 mm posteriorly (< –2 mm). The accuracy of screw placement was assessed using CT imaging in the axial plane, and the proportion of screws penetrating a vertebral foramen or a transverse foramen was compared between the 3 groups. Screw loosening was defined as a lucent zone around the screw evaluated on cervical radiography at 1 year after surgery. Complications related to PVFS insertion and revision surgery related to PVFS were evaluated. RESULTS The authors classified 25 PVFSs into the longer group, 43 into the intermediate group, and 26 into the shorter group. The proportion of screws penetrating a vertebral foramen was largest in the shorter group, and the proportion penetrating a transverse foramen was largest in the longer group. Screw loosening was confirmed for 3 of 94 PVFSs. One PVFS inserted in C6 unilaterally within a long construct from C2 to C7 showed loosening, but it did not cause clinical symptoms. Revision surgery was required for 2 PVFSs inserted in C3 bilaterally as the lower instrumented vertebra in occiput–cervical fusion because they pulled out. There was no neurovascular complication related to PVFS insertion. CONCLUSIONS PVFSs are useful for posterior cervical fusion surgery as alternative anchor screws, and the line of the posterior wall of the cervical body on lateral fluoroscopic images is a potential intraoperative reference to indicate an appropriate trajectory for PVFSs.

Background: Estimating the nutritional content of food is essential for self-management in people with type 2 diabetes mellitus, but it is a difficult skill to learn. The aim of this study was to investigate how diabetes management was impacted by the ability of patients to search for items they ate from a database of 26,300 different foods, and to visualize nutritional intake using the Japanese mobile application (app) "Calomeal." Methods: This was a single-arm, single-center, pilot study. Eighteen outpatients with type 2 diabetes mellitus used the "Calomeal" app for 3 months. The primary endpoint was change in hemoglobin A1c (HbA1c). Secondary endpoints were changes in body weight (BW), lipid parameters, and quality of life scores. Results: The baseline characteristics of the study subjects were as follows: age: 53.4 ± 7.8 years; male/female ratio: 11/7; HbA1c: 7.9 (7.58 - 8.23)%; and body mass index (BMI): 25.17 (21.63 - 28.59) kg/m 2 . Significant reductions in HbA1c and BMI were observed over 3 months (HbA1c: 7.9 (7.58 - 8.23)% to 7.6 (7.3 - 8.23)%, P = 0.0410; BMI: 25.17 (21.63 - 28.59) to 24.54 (21.57 - 27.81) kg/m 2 , P = 0.0057). Reductions in HbA1c and BMI both correlated with decreased carbohydrate intake estimated by the mobile app. Conclusions: Japanese patients who used their smartphones to visualize their nutritional intake using the "Calomeal" app demonstrated improved short-term glycemic control and BMI. Although the validity of the results should be tested in future randomized controlled trials, this approach may be a clinical option for improving self-management in Japanese patients with type 2 diabetes mellitus. J Clin Med Res. 2021;13(8):425-433 doi: https://doi.org/10.14740/jocmr4558

We aimed to develop a machine learning (ML) model for predicting the neurological outcomes of cervical spinal cord injury (CSCI). We retrospectively analyzed 135 patients with CSCI who underwent surgery within 24 h after injury. Patients were assessed with the American Spinal Injury Association Impairment Scale (AIS; grades A to E) 6 months after injury. A total of 34 features extracted from demographic variables, surgical factors, laboratory variables, neurological status, and radiological findings were analyzed. The ML model was created using Light GBM, XGBoost, and CatBoost. We evaluated Shapley Additive Explanations (SHAP) values to determine the variables that contributed most to the prediction models. We constructed multiclass prediction models for the five AIS grades and binary classification models to predict more than one-grade improvement in AIS 6 months after injury. Of the ML models used, CatBoost showed the highest accuracy (0.800) for the prediction of AIS grade and the highest AUC (0.90) for predicting improvement in AIS. AIS grade at admission, intramedullary hemorrhage, longitudinal extent of intramedullary T2 hyperintensity, and HbA1c were identified as important features for these prediction models. The ML models successfully predicted neurological outcomes 6 months after injury following urgent surgery in patients with CSCI.

Prediction of the neurological prognosis of cervical spinal cord injury (CSCI) is useful for setting treatment goals. This study aimed to develop a machine learning (ML) model for predicting neurological outcomes of CSCI. We retrospectively analyzed 135 patients with CSCI who underwent surgery within 24 hours after injury. American Spinal Injury Association impairment scales (AIS; grades A to E) were analyzed 6 months after injury as primary outcome measures. A total of 33 features extracted from demographic variables, surgical factors, laboratory variables, neurological status, and radiological findings were analyzed. The multiclass ML model was created using Light GBM, XGBoost, and CatBoost. The accuracy, recall, precision, and F1 score were calculated for each classification model. We evaluated Shapley Additive Explanations (SHAP) values to determine the variables that contributed the most to the prediction models. Of the ML models used, CatBoost had the highest accuracy (0.807), recall (0.574), precision (0.808), and F1 score (0.622). AIS grade at admission, intramedullary hemorrhage, longitudinal extent of intramedullary T2 hyperintensity, total motor index score of the lower extremity, and HbA1c were identified as important features for the prediction model. The ML models successfully predicted neurological outcomes for five grades of AIS 6 months after injury.

Objectives To describe the novel technique of continuous local antibiotic perfusion (CLAP) for a surgical site infection (SSI) after instrumented spinal surgery. Methods CLAP was applied to 4 continuous patients at our institution who developed SSI after instrumented spinal surgery. Results All 4 patients were successfully treated and the infection was controlled. The implant was retained in all patients. The duration of CLAP ranged from 2 to 3 weeks. The blood level of the antibiotic used (gentamicin) at 1 week after the initiation of CLAP did not increase in any patient. No other adverse events occurred in any patient. Dramatic improvements in laboratory parameters, including the white blood cell (WBC) counts and C-reactive protein (CRP) levels were seen in every patient at 1 week after the initiation of CLAP. Conclusions CLAP controlled the infection without severe adverse events in all 4 patients, and the implants were retained. Despite its cost and the discomfort of patients, CLAP may become an option for the treatment of SSIs after instrumented spinal surgery. A large number of case series are needed to verify the efficacy of CLAP for patients with SSIs after instrumented spinal surgery.

The use of methotrexate (MTX) to treat rheumatoid arthritis (RA) is increasing. Recently, MTX-associated lymphoproliferative disorder (MTX-LPD) has been frequently reported as lymphoma occurring during MTX therapy. The authors report their experience with a relatively rare case of MTX-LPD presenting in the lumbar spine. The patient, a 73-year-old woman who experienced low-back pain while receiving MTX therapy for RA, was suspected of having developed MTX-LPD based on her medical history, images of the L1 vertebra, and transpedicular biopsy results. One week after discontinuing MTX, the patient’s low-back pain reportedly improved. The woman was diagnosed with MTX-LPD based on histopathological findings. MTX discontinuation alone coincided with spontaneous tumor regression. Because MTX-LPD can occur in tissues other than lymph nodes, such as in bones and joints, it is a disease that should be considered when diagnosing spinal tumors in patients receiving MTX therapy.

Background A high-riding vertebral artery (HRVA) is an intraosseous anomaly that narrows the trajectory for C2 pedicle screws. The prevalence of a HRVA is high in patients who need surgery at the craniovertebral junction, but reports about HRVAs among subaxial cervical spine disorders are limited. We sought to determine the prevalence of HRVAs among patients with subaxial cervical spine disorders to elucidate the potential risk for VA injury in subaxial cervical spine surgery. Methods We included 215 patients, 94 were with a main lesion from C3 to C7 (subaxial group) and 121 were with a main lesion from T1 to L5 (thoracolumbar group). A HRVA was defined as a maximum C2 pedicle diameter of Results The patients of subaxial group were younger than those of the thoracolumbar group but the sex and BMI didn’t differ significantly between the 2 groups. The osteoarthritis grade of C1/2 facet joints of the subaxial group was statistically higher than the thoracolumbar group. A HRVA was found in 26 patients of 94 (27.7 %) in the subaxial group and in 19 of 121 (15.7%) in the thoracolumbar group. The prevalence of a HRVA in the subaxial group was statistically higher and logistic regression analysis indicated that osteoarthritis of C1/2 facet joints significantly correlated with HRVA. Conclusions The prevalence of a HRVA in patients with subaxial cervical spine disorders is higher than in those without cervical spine disorders, and osteoarthritis of C1/2 facet joints significantly correlated with a HRVA.

The aim of this study was to investigate the effects of 24-week synbiotic supplementation on chronic inflammation and the gut microbiota in obese patients with type 2 diabetes. We randomized 88 obese patients with type 2 diabetes to one of two groups for 24 weeks: control or synbiotic (Lacticaseibacillus paracasei strain Shirota (previously Lactobacillus casei strain Shirota) and Bifidobacterium breve strain Yakult, and galactooligosaccharides). The primary endpoint was the change in interleukin-6 from baseline to 24 weeks. Secondary endpoints were evaluation of the gut microbiota in feces and blood, fecal organic acids, high-sensitivity C-reactive protein, lipopolysaccharide-binding protein, and glycemic control. Synbiotic administration for 24 weeks did not significantly affect changes in interleukin-6 from baseline to 24 weeks (0.35 ± 1.99 vs. −0.24 ± 1.75 pg/mL, respectively). Relative to baseline, however, at 24 weeks after synbiotic administration there were positive changes in the counts of Bifidobacterium and total lactobacilli, the relative abundances of Bifidobacterium species such as Bifidobacterium adolescentis and Bifidobacterium pseudocatenulatum, and the concentrations of acetic and butyric acids in feces. No significant changes in inflammatory markers were found in the synbiotic group compared to the control group. However, synbiotic administration at least partially improved the gut environment in obese patients with type 2 diabetes.

Background: The estimation of nutrient content is difficult, but important for self-management of people with type 2 diabetes mellitus (T2DM). In Japan, food-log app has not been penetrated as a treatment tool yet. That could be because Japanese food is diverse and consists of various ingredients. In this study, we investigated the efficacy of app “Calomeal” that enables the patients to search for what they eat among the database of 26300 kinds of foods and to visualize the nutrients using smartphone. Method: We recruited 20 people with T2DM in Juntendo University. They used this app for 3 months on the regular treatment. The blood and urine exams were performed monthly. At the beginning and the end of the study, the estimation of food was also assessed by the dietitian and the questionnaires about QOL (DTSQ/PAID) were performed. Results: 2 were dropped out. 18 participants were 52.3±9.2 y.o., male/female 12/8, BMI 25.8±4.7 kg/m2, and HbA1c 8.1±0.4%. At the end of study, significant reduction was observed in HbA1c and BMI (7.92±0.4 to 7.75±0.5%[p=0.0410], 25.69±5.0 to 25.10±4.8 kg/m2 [p=0.0057]). Reduction of HbA1c and BMI were both correlated to the reduction of carbohydrate (r=0.5018 [p=0.0338], r =0.5542 [p=0.0170]). High correlation was also observed between the reduction of carbohydrate and calorie (r=0.8167 [p Conclusion: Visualizing nutrients via Calomeal improved glycemic control and BMI by reducing over intake. It is of note that in some Japanese people, the adjusting nutrient intake by raising the calorie may contribute to their QOL. Disclosure A. Tsunemi: None. J. Sato: Research Support; Self; Sanofi. Speaker’s Bureau; Self; Daiichi Sankyo, Medtronic, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. M. Enomoto: None. Y. Iwagaki: None. S. Sugimoto: None. Y. Someya: None. M. Kiya: None. E. Matsuhashi: None. Y. Wakabayashi: None. T. Funayama: None. T. Uchida: None. T. Miyatsuka: None. K. Azuma: None. T. Shimizu: None. H. Satoh: None. A. Kanazawa: Speaker’s Bureau; Self; Novartis Pharma K.K., Sanofi, Takeda Pharmaceutical Company Limited. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.

BACKGROUND There have been many reports of heart failure due to diabetic cardiomyopathy and decreased left ventricular (LV) function with increasing age in patients with type 1 diabetes mellitus (T1DM). Recently, although left atrial (LA) function has been occasionally reported to be a more useful prognostic indicator than LV function in acquired heart diseases, LA function in patients with T1DM has not yet been studied. PURPOSE To investigate LA dysfunction in patients with T1DM. METHODS Fifty patients with T1DM were recruited (age, 5–41 years). We excluded patients who had a history of heart disease, hypertension, and those taking cardioprotective agents. The patients and 50 age-matched controls were classified into 3 age groups (D1, C1, 5–14 years; D2, C2, 15–29 years; D3, C3, 30–41 years). The LA phasic function serving as the reservoir, conduit, and pump strains; the LA strain rate (SR) in the systole, early diastole, and late diastole; and the LV global longitudinal strain (LV-LS) as determined via 2-dimensional speckle tracking imaging were measured from the apical four- and two-chamber views. We also calculated the LA stiffness index as the ratio of E/e’ to the LA reservoir strain. RESULTS There was no significant difference in left ventricular ejection fraction in each age group. The LA reservoir strains in D2 and D3 were significantly lower than those in C2 (40.8 ± 5.7% vs. 47.2 ± 5.5%, p = 0.005) and C3 (39.2 ± 5.5% vs. 47.3 ± 5.7%, p = 0.004), respectively. The LA conduit strain in D2 was significantly lower than that in C2 (28.9 ± 5.8% vs. 35.0 ± 5.0%, p = 0.006). The LA pump strain and the three phases of LA SR were not significantly different among the age groups. The LA stiffness index in D3 increased significantly compared to that in N3 (0.18 ± 0.05 vs. 0.13 ± 0.01, p CONCLUSIONS The LA reservoir strain might be as useful as LV-LS as an early marker of cardiac dysfunction in patients with T1DM. The correlation coefficient between the LA reservoir strain and LV-LS was not strong. Therefore, although LV-LS might affect the LA reservoir strain, it might represent other aspects of cardiac dysfunction. The increase of LA stiffness might represent the changes in LA wall properties and could be another useful indicator of cardiac dysfunction during long-term follow-ups, which is independent of LV-LS. Overall, these findings provide new insights into cardiac dysfunction in patients with T1DM.

Background A high-riding vertebral artery (HRVA) is an intraosseous anomaly that narrows the trajectory for C2 pedicle screws. The prevalence of a HRVA is high in patients who need surgery at the craniovertebral junction, but reports about HRVAs in subaxial cervical spine disorders are limited. We sought to determine the prevalence of HRVAs among patients with subaxial cervical spine disorders to elucidate the potential risk for VA injury in subaxial cervical spine surgery. Methods We included 215 patients, 94 were with a main lesion from C3 to C7 (subaxial group) and 121 were with a main lesion from T1 to L5 (thoracolumbar group). A HRVA was defined as a maximum C2 pedicle diameter of Results The patients in the subaxial group were younger than those in the thoracolumbar group, but their sex and BMI did not differ significantly between the 2 groups. The mean osteoarthritis grade of the C1-2 facet joints of patients in the subaxial group was significantly higher than that in those in the thoracolumbar group. A HRVA was found in 26 patients of 94 (27.7 %) in the subaxial group and in 19 of 121 (15.7 %) in the thoracolumbar group. The prevalence of a HRVA in the subaxial group was significantly higher and osteoarthritis of C1-2 facet joints correlated significantly with a HRVA. Conclusions The prevalence of a HRVA in patients with subaxial cervical spine disorders is higher than in those without and osteoarthritis of the C1-2 facet joints is correlated with a HRVA.

Summary Background & aims The usefulness of low-carbohydrate diet (LCD) for Japanese patients with type 2 diabetes mellitus (T2DM) has not been fully investigated. Therefore, we compared the effectiveness and safety of LCD with calorie restricted diet (CRD). Methods This prospective, randomized, open-label, comparative study included 66 T2DM patients with HbA1c >7.5% even after receiving repeated education programs on CRD. They were randomly allocated to either the 130g/day LCD group (n = 33) or CRD group (n = 33). Patients received personal nutrition education of CRD or LCD for 30 min at baseline, 1, 2, 4, and 6 months. Patients of the CRD group were advised to maintain the intake of calories and balance of macronutrients (28× ideal body weight calories per day). Patients of the LCD group were advised to maintain the intake of 130 g/day carbohydrate without other specific restrictions. Several parameters were assessed at baseline and 6 months after each intervention. The primary endpoint was a change in HbA1c level from baseline to the end of the study. Results At baseline, BMI and HbA1c were 26.5 (24.6–30.1) and 8.3 (8.0–9.3), and 26.7 (25.0–30.0) kg/m 2 and 8.0 (7.6–8.9) %, in the CRD and LCD, respectively. At the end of the study, HbA1c decreased by −0.65 (−1.53 to −0.10) % in the LCD group, compared with 0.00 (−0.68 to 0.40) % in the CRD group (p 2 ] exceeded that observed in the CRD group (p = 0.03). Conclusions Our study demonstrated that 6-month 130 g/day LCD reduced HbA1c and BMI in poorly controlled Japanese patients with T2DM. LCD is a potentially useful nutrition therapy for Japanese patients who cannot adhere to CRD. This trial was registered at http://www.umin.ac.jp/english/ (University Hospital Medical Information Network: study ID number 000010663).

We present classical molecular dynamics (MD) and first principles molecular dynamics (FPMD) studies to investigate the transport mechanisms of hydroxide ions through poly(arylene ether sulfone ketone)s containing quaternized ammonio-substituted fluorenyl groups (QPE) as anion exchange polymers used in applications such as alkaline fuel cells. The effect of the number of repeating units in QPE on the ion conductivity of hydroxide ions was investigated by classical MD. Calculated ion conductivities are almost the same regardless of the number of repeating units in QPE and are consistent with the experimental values. The microscopic structures of water distribution in hydrated QPE were also investigated. Analysis of radial distribution functions (RDFs) of atoms calculated by classical MD implies the possibility of two different interacting conformations of hydroxide ions and ammonium groups in hydrated QPE. Distinct peaks in the RDF of O(hydroxide ion)–N(QPE) means that diffusion of hydroxide ions in hydrated QPE is mainly governed by surface diffusion, i.e., hopping between the ammonium groups of QPE, when the vehicle transport occurs. Transport of hydroxide ions based on the Grotthuss mechanism was also investigated by FPMD. The results show that hydroxide ion transport occurs with the formation of H 3 O 2 − through the hydrogen network of the water molecules. The formed H 3 O 2 − cleaves into H 2 O and OH − , resulting in proton exchange between a water molecule and a hydroxide ion, which is similar to the proton transfer mechanism observed in proton exchange membranes.

A 77-year-old man with paroxysmal atrial fibrillation and hypertrophic obstructive cardiomyopathy was scheduled for cervical laminoplasty. He was predicted difficult mask ventilation combined with difficult laryn- goscopy (CICV) because of short thyromental distance. After induction of general anesthesia, we attempted tracheal intubation using McGRATHO and Gum-elastic Bougie and the intubation was successful. After opera- tion, in ward, atrial fibrillation occurred. Because anti- arrhythmic agents were not effective, cardioversion was planned. While under sedation, his breathing stopped. The attending physician could not ventilate with mask and intubate with Macintosh laryngoscope. The patient went into cardiopulmonary arrest After successful intubation using McGRATH? and Gum- elastic Bougie by anesthesiologist The attending physi- cian did not recognize CICV. We should convey infor- mation of CICV surely and perform education about difficult airway management.

Aims Olfactory dysfunction is associated with the transition from normal cognition to dementia in persons without type 2 diabetes. This study aimed to investigate whether olfactory dysfunction could be an early marker of future dementia in older patients with type 2 diabetes. Methods This exploratory study included 151 older Japanese outpatients with type 2 diabetes who did not have a diagnosis of probable dementia at baseline. A multivariate logistic regression model was used to determine whether Open Essence (OE) test score at baseline is associated with the development of probable dementia. Results Over 3 years, approximately 9% of the study subjects developed probable dementia. Subjects with olfactory dysfunction at baseline developed probable dementia more frequently than those without. Multivariate logistic regression showed that lower OE test score, higher age, lower Mini-Mental State Examination (MMSE) score, higher total protein concentration, and more frequent use of a sulfonylurea are significantly associated with the development of probable dementia. Stepwise multivariate regression analysis demonstrated that change in OE test score over 3 years is significantly associated with change in MMSE score. Conclusions Our study suggested that olfactory dysfunction precedes the development of probable dementia in older patients with type 2 diabetes.

Objectives To assess the effect of treatment guidance based on data from a continuous glucose monitoring (CGM) device on glycaemic control, and patient satisfaction, in patients with type 2 diabetes mellitus (T2DM). Methods Patients with poorly-controlled T2DM treated with insulin were randomly assigned to the intervention or nonintervention group. Continuous blood-glucose levels were recorded for 4–5 days using a CGM device on three separate occasions during the 8-month study period. The intervention group received treatment guidance based on the CGM data; the nonintervention group received advice based on blood glucose and glycosylated haemoglobin (HbA1c) levels. Results A total of 34 patients were enrolled in the study. The mean ± SD baseline HbA1c was 8.2 ± 1.2% in the intervention group and 8.2 ± 0.9% in the nonintervention group. At the study end, there was no significant difference in the change from baseline of HbA1c between the two groups. There was also no significant difference in the change from baseline in the Diabetes Treatment Satisfaction Questionnaire score between the two groups. Conclusions The present study did not demonstrate that treatment guidance using retrospective CGM data was effective for improving glycaemic control and therapeutic satisfaction in Japanese patients with T2DM.

Nocturnal hypoglycemia is a serious problem in the management of diabetes mellitus (DM). The average daily risk range (ADRR) was the value created to access blood glucose variability. ADRR can be calculated using self-monitoring blood glucose (SMBG) values and is reported to be sensitive to both hyperglycemia and hypoglycemia. However, the usefulness of ADRR in Asian type 1 patients with DM (T1DM) to detect nocturnal hypoglycemia has not been elucidated yet. In this study, we recruited 28 Japanese T1DM. All patients wore outpatient continuous glucose monitoring (CGM) for 6 days and performed SMBG, 3 times/day (before breakfast and dinner, and 2 hours after dinner) for 14 days. Based on these SMBG data, we calculated ADRR and assessed the correlation of ADRR with glucose kinetics. There were no significant correlations of ADRR with hypoglycemic and hyperglycemic frequencies during nighttime. However, there were significant correlations of ADRR with Standard Deviation (SD) (r=0.53, p = 0.003), and Coefficient of Variation (CV) (r=0.46, p = 0.015) of mean glucose during nighttime. In addition, although ADRR showed no significant correlation with hypoglycemic frequency during daytime, ADRR showed significant correlation with hyperglycemic frequency (r=0.47, p=0.012), mean glucose (r=0.40, p=0.033), SD (r=0.56, p = 0.002) and CV (r=0.39, p = 0.041) during daytime. In conclusion, ADRR could be useful to detect glycemic variability during nighttime, however, it is useless to estimate risks of hypoglycemia and hyperglycemia during nighttime. Our data showed only limited usefulness of ADRR in clinical setting in Japanese T1DM. Disclosure F. Ikeda: None. A. Kanazawa: Speaker's Bureau; Self; Sanofi K.K., Kissei Pharmaceutical Co., Ltd.. M. Iida: None. H. Kaga: None. N. Takayanagi: None. T. Shimizu: None. C. Shirakawa: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.

This study investigated the safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin (100 mg/day) and low-dose metformin (500 or 750 mg/day).Fifty patients were randomly allocated to the control group (maintaining the initial low-dose of metformin) and the dose increase group (up-titrating of metformin to 1,500-2,250 mg/day) for 24 weeks. The primary outcome was change in HbA1c from baseline to 24 weeks.Among the 25 patients allocated to the dose increase group, four patients were not able to complete the study protocol because of gastrointestinal symptoms. HbA1c in the dose increase group was significantly but modestly lower than in the control group (change in HbA1c: 0.22 ± 0.57 vs. -0.15 ± 0.58%, group comparison, P 0.05). The dose increase group did not gain weight during the study period, and no hypoglycemic events were reported in both groups. The rate of gastrointestinal symptoms in the dose increase group was profoundly higher than in the control group (32 vs. 0%, P 0.01).In Japanese patients with type 2 diabetes treated with vildagliptin and low-dose metformin, metformin up-titration significantly but modestly improved glycemic control without hypoglycemia and weight gain.

The aim of this study was to investigate the efficacy of insulin degludec used for basal-bolus insulin regimen after switching from twice-daily basal insulin in Japanese patients with type 1 diabetes mellitus. The subjects were 22 type 1 diabetes patients treated with basal-bolus insulin regimen with twice-daily basal insulin. Basal insulin was switched to once-daily injection of insulin degludec with 10% dose reduction. HbA1c and fasting plasma glucose (FPG) were measured before and 12 weeks after switching. The frequency of hypoglycemic episodes, standard deviation (SD) of blood glucose, and mean of daily difference (MODD) were evaluated by continuous glucose monitoring (CGM) before and 4 weeks after switching. HbA1c and FPG before and 12 weeks after switching were comparable (HbA1c 8.5 ± 1.4 versus 8.7 ± 1.6%,P=0.28; FPG 203.2 ± 81.2 versus 206.5 ± 122.4 mg/dL,P=0.91). The frequency of hypoglycemia during nighttime was not significantly different at 4 weeks after switching (14.4 ± 17.0 versus 11.1 ± 15.0%,P=0.45). In addition, SD and MODD before and 4 weeks after switching were also comparable. In conclusion, glycemic control under once-daily insulin degludec injection was almost comparable to that under twice-daily basal insulin injections in Japanese type 1 diabetes patients. This study was registered with ID:UMIN000010474.

Aims Recent clinical studies identified the relation between olfactory dysfunction and cognitive impairment in the elderly without type 2 diabetes mellitus. The aim of the present study was to define the relation between olfactory function and cognition in elderly patients with type 2 diabetes mellitus. Methods The study participants comprised 250 elderly (age, 68–77, median 72) Japanese outpatient with type 2 diabetes mellitus free of clinically-evident cognitive impairment. Olfactory and cognitive functions were evaluated by the Open Essence (OE) test and Mini-mental State Examination (MMSE), respectively. Results Based on the MMSE score, 62.0%, 24.4%, and 13.6% of the participants were considered to have no impairment, possible cognitive impairment and probable dementia, respectively. The OE test score of the probable dementia group was significantly lower than other groups. Furthermore, age and serum uric acid were significantly higher in the probable dementia group than other groups. Simple correlation analysis showed positive correlation between the MMSE score and diastolic blood pressure, education, OE test score, total cholesterol, LDL cholesterol, folic acid, and negative correlation with age, HbA 1c , aspartate aminotransferase, serum adiponectin and urinary albumin excretion. Multivariate regression analysis showed that OE test score correlated significantly and independently with MMSE score (standardized coefficients β = 0.542, R 2 = 0.478, P Conclusions The results suggested the association of olfactory dysfunction with cognitive impairment in elderly patients with type 2 diabetes mellitus.

OBJECTIVE Mounting evidence indicates that the gut microbiota are an important modifier of obesity and diabetes. However, so far there is no information on gut microbiota and “live gut bacteria” in the systemic circulation of Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Using a sensitive reverse transcription–quantitative PCR (RT-qPCR) method, we determined the composition of fecal gut microbiota in 50 Japanese patients with type 2 diabetes and 50 control subjects, and its association with various clinical parameters, including inflammatory markers. We also analyzed the presence of gut bacteria in blood samples. RESULTS The counts of the Clostridium coccoides group, Atopobium cluster, and Prevotella (obligate anaerobes) were significantly lower (P < 0.05), while the counts of total Lactobacillus (facultative anaerobes) were significantly higher (P < 0.05) in fecal samples of diabetic patients than in those of control subjects. Especially, the counts of Lactobacillus reuteri and Lactobacillus plantarum subgroups were significantly higher (P < 0.05). Gut bacteria were detected in blood at a significantly higher rate in diabetic patients than in control subjects (28% vs. 4%, P < 0.01), and most of these bacteria were Gram-positive. CONCLUSIONS This is the first report of gut dysbiosis in Japanese patients with type 2 diabetes as assessed by RT-qPCR. The high rate of gut bacteria in the circulation suggests translocation of bacteria from the gut to the bloodstream.

The aza-Clasen rearrangement of N-aryl-2-vinylazetidines has been explored. N-Aryl-2-vinylazetidines were transformed to corresponding tetrahydrobenzazocines in good yields. Unexpectedly, the tetrahydrobenzazocine was unstable and readily isomerized to vinyltetrahydroquinoline in the presence of acid. The mechanism of this ring contraction was studied in detail.

The aza-Prins reaction of 3-vinyltetrahydroquinolines with aldehydes proceeded smoothly in the presence of hydrogen halides, and the tricyclic benzazocine derivatives were isolated in good to high yields. The reaction would proceed through the formation and cyclization of the iminium ion intermediate.

Overall adiposity is associated with insulin resistance. Decline in insulin sensitivity induces a compensatory increase in insulin secretion from beta cells. The impact of adipose tissue distribution, i.e., visceral versus subcutaneous fat, on beta cell function remains to be elucidated. The aim of this study was to retrospectively investigate the relation between the areas of subcutaneous and visceral fat and the increment in C-peptide levels (CPR) during glucagon load (ΔCPR) in Japanese patients with type 2 diabetes. In 195 Japanese patients with type 2 diabetes, beta cell function was evaluated by ΔCPR, CPR index (100 × fasting CPR divided by fasting glucose), and 24-h urinary C-peptide excretion (U-CPR) during the 1-week hospitalization for diabetes education. Then, we investigated the relationships between markers of beta cell function and the areas of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) determined by abdominal computed tomography. Stepwise multiple regression analyses identified SAT, but not VAT, as an independent variable of both ΔCPR and U-CPR [standard regression coefficient (Stdβ) = 0.332, P < 0.01 for ΔCPR, and Stdβ = 0.181, P < 0.05 for U-CPR], and both SAT and VAT were identified as independent variables for CPR index (Stdβ = 0.253, P < 0.01 for SAT, and Stdβ = 0.193, P < 0.01 for VAT). Our results indicated that SAT is independently correlated with beta cell function by glucagon test in Japanese patients with type 2 diabetes.

Previous studies reported that both cilnidipine and azelnidipine have a renoprotective effect compared with amlodipine. The aim of this study was to compare the effects of cilnidipine and azelnidipine on blood pressure, heart rate and albuminuria. An open‐label prospective crossover trial was carried out. We recruited 19 type 2 diabetics treated with amlodipine (5 mg/day) at least for 12 weeks. At study entry, amlodipine was changed to cilnidipine (10 mg/day) or azelnidipine (16 mg/day) and each administered for 16 weeks. Then, the drugs were switched and the treatment was continued for another 16 weeks. Despite no differences in 24‐h blood pressure and heart rate between cilnidipine and azelnidipine, treatment with cilnidipine resulted in a greater reduction in urinary albumin:creatinine ratio than azelnidipine. Our results suggested that cilnidipine is more efficient in reducing albuminuria than azelnidipine independent of its blood pressure lowering effect in type 2 diabetic patients with hypertension. This trial was registered with UMIN (no. 000007201).

BACKGROUND The aim of this study was to assess the relationship between masked hypertension (MHT) and vascular damage in patients with type 2 diabetes. METHODS The study subjects were patients with type 2 diabetes who were normotensive based on blood pressure (BP) measurement in the clinic (n = 80) without antihypertensive drugs and free of retinopathy, macroalbuminuria, overt cardiovascular disease. Subjects underwent 24-h ambulatory blood pressure monitoring (ABPM), measurement of flow-mediated dilatation (FMD), and brachial-ankle pulse wave velocity (baPWV). Based on the results of ABPM, subjects with mean daytime systolic BP ≥135 and/or 85 mm Hg were defined as MHT and their clinical data were compared with those of normotensive patients (NT). The data were also compared with those of type 2 diabetic patients with hypertension (HT) as measured in the clinic (n = 32). RESULTS MHT was detected in 47.5% of the study subjects with normotension at clinic (n = 38). Impaired FMD (5.65 ± 2.00% for NT, 4.26 ± 1.88% for MHT, 3.90 ± 1.71% for HT, P < 0.001) and higher baPWV (1,514.2 ± 212.7 cm/s for NT, 1,749.9 ± 339.7 cm/s for MHT, and 1,768.6 ± 302.8 cm/s for HT, P < 0.001) were similarly noted in patients with MHT and HT compared with NT. Multivariate regression analysis indicated that daytime systolic BP measured by ABPM, the estimated duration of diabetes and serum triglycerides were significantly associated with FMD and daytime systolic BP measured by ABPM, not systolic BP at clinic, age, and HbA(1c) were significantly associated with baPWV. CONCLUSIONS Given that patients with impaired FMD and higher baPWV are known to be at higher risk of cardiovascular disease, our data suggest that type 2 diabetic patients with MHT could be also at increased risk of cardiovascular disease.

Background: Ezetimibe-plus-statin therapy has been reported to provide greater reduction in low-density lipoprotein cholesterol (LDL-C) level than statin monotherapy. The aim of the present study was to evaluate the relationship between LDL-C lowering effect and baseline cholesterol absorption and synthesis markers in patients with coronary artery disease (CAD). Methods and Results: A total of 171 patients with CAD whose LDL-C level was ≥100mg/dl after treatment with atorvastatin (10mg/day) or rosuvastatin (2.5mg/day) for 4 weeks were assigned to additionally receive ezetimibe (10mg/day) plus a statin or a double dose of statin for 12 weeks. The decreases in LDL-C (-30.0±15.6mg/dl vs. -19.2±14.2mg/dl) and the ratio of campesterol, an absorption marker, to total cholesterol levels (-1.35±0.90μg/mg vs. 0.33±0.74μg/mg) were greater in the ezetimibe-plus-statin group (P

The aim of our study was to investigate clinical factors associated with the development of chronic kidney disease (CKD) in Japanese type 2 diabetes patients diagnosed by the new equation established by the Japanese Society of Nephrology. We analyzed data collected from 653 Japanese patients with type 2 diabetes who were followed at Juntendo University Hospital for 2 years to determine the risk factors for new-onset CKD and 2-year eGFR decline from the baseline. CKD developed de novo in 56 diabetic patients, whereas 288 patients showed no signs of CKD at the end of the 2-year follow-up period. The 2-year cumulative incidence of newly diagnosed cases with CKD was 8.6%. Of these, the transition rate to albuminuria was 73.2%, the proportion of patients who developed low eGFR (

Background & aims Recently, we conducted a prospective randomized controlled trial (RCT) showing that a 6-month 130g/day low-carbohydrate diet (LCD) reduced HbA1c and BMI more than a calorie restricted diet (CRD). [1] To assess whether the benefits of the LCD persisted after the intensive intervention, we compared HbA1c and BMI between the LCD and CRD groups at 1 year after the end of the 6-month RCT. Methods Following the end of the 6-month RCT, patients were allowed to manage their own diets with periodic outpatient visits. One year later, we analyzed clinical and nutrition data. Results Of the 66 participants in the original study, 27 in the CRD group and 22 in the LCD group completed this trial. One year after the end of the original RCT, the carbohydrate intake was comparable between the groups (215 [189–243]/day in the CRD group and 214 (176–262) g/day in the LCD group). Compared with the baseline data, HbA1c and BMI were decreased in both groups (CRD: HbA1c -0.4 [-0.9 to 0.3] % and BMI -0.63 [-1.20 to 0.18] kg/m2; LCD: HbA1c -0.35 [-1.0 to 0.35] % and BMI -0.77 [-1.15 to -0.12] kg/m2). There were no significant differences in HbA1c and BMI between the groups. Conclusions One year after the diet therapy intervention, the beneficial effect of the LCD on reduction of HbA1c and BMI did not persist in comparison with CRD. However, combining the data of both groups, significant improvements in HbA1c and BMI from baseline were observed. Although the superiority of the LCD disappeared 1 year after the intensive intervention, these data suggest that well-constructed nutrition therapy programs, both CRD and LCD, were equally effective in improving HbA1c for at least 1 year. Trial registration University Hospital Medical Information Network (UMIN) ID000010663

Glimepiride is a potent sulfonylurea agent and is widely used for type 2 diabetic patients, however, the safety and efficacy of glimepiride in patients with fair diabetic control (HbA1c level: 6.5-7.9%) have not been investigated so far. Therefore, we investigated the safety and efficacy of glimepiride titration using self-monitoring blood glucose (SMBG) in the achievement of strict glycemic control in fairly controlled diabetic patients. Japanese type 2 diabetic patients who were diet-controlled or treated with alpha-glucosidase inhibitor or metformin, were randomly assigned into the SMBG group with titration of glimepiride using SMBG, or the conventional therapy group (control group) without SMBG. Glimepiride was initiated at a dose of 0.5 mg/day and plasma glucose, insulin, HbA1c, and glycoalbumin levels were evaluated for 6 months in both groups. The dose of glimepiride was titrated in the SMBG group according to the SMBG levels before breakfast and dinner. The mean dose of glimepiride at 6 months tended to be higher in the SMBG than the control group (1.0±0.8 vs 0.6±0.3mg/day), but not significant. At 6 months after glimepiride treatment, HbA1c levels were significantly lower than at baseline (SMBG: 7.2±0.5 vs 6.5±0.6%, n=23, P

The door-to-balloon time (DTB) is an important predictor of the outcome for patients with ST-elevation myocardial infarction (STEMI). In Japan, percutaneous coronary intervention (PCI) can be performed at many hospitals, and the predominant strategy for reperfusion therapy is primary PCI. However, it remains unclear how rapidly reperfusion is achieved at these hospitals.The study group comprised 369 patients with STEMI who presented within 12 h of symptom onset to a tertiary emergency center (TEC) or at 11 community hospitals (CHs) in 2006 and underwent emergency coronary angiography. Median DTB was shorter in the TEC (63 vs 104 min, P0.001), and the rate of DTB within 90 min was higher in the TEC (96% vs 39%, P0.001). Lateral myocardial infarction, presentation during off-hours, and non-cardiologist as the first-contact physician were significantly associated with a prolonged DTB in CHs. There was a trend toward lower 30-day mortality from all causes in the TEC (2.0% vs 4.8%, P=0.08). Multiple logistic regression analysis demonstrated that prolonged DTB (90 min) was an independent predictor of 30-day mortality (odds ratio 12.6; 95% confidence interval 1.85-86.2, P=0.01).Establishment of emergency cardiac care systems with the goal of DTB within 90 min is required in PCI-capable hospitals to improve clinical outcomes.