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BackgroundThe prevalence of diabetes is rising, and diabetes develops at a younger age in East Asia. Although lower limb amputation negatively affects quality of life and increases the risk of cardiovascular events, little is known about the rates and predictors of amputation among persons with diabetes from young adults to those in the “young-old” category (50–72 y).MethodsWe analyzed data from a nationwide claims database in Japan accumulated from 2008 to 2016 involving 17,288 people with diabetes aged 18–72 y (mean age 50.2 y, HbA1c 7.2%). Amputation occurrence was determined according to information from the claims database. Cox regression model identified variables related to lower limb amputation.ResultsThe mean follow-up time was 5.3 years, during which time 16 amputations occurred (0.17/1000 person-years). Multivariate Cox regression analysis showed that age (hazard ratio [HR] 1.09 [95% confidence intervals] 1.02–1.16,p = 0.01) and HbA1c (HR 1.46 [1.17–1.81],p ConclusionsAge and HbA1c were associated with amputations among diabetic individuals, and the rates of amputation were significantly greater in those ≥60 years old and with HbA1c ≥8.0%.

Aims Little is known about the relationship between medication adherence for oral hypoglycemic agents (OHAs) and glycemic control after adjusting healthy adherer effect in large scale study. Thus, adjusting for health-related behaviors, we investigated the clinical variables associated with medication adherence and the relationship between medication adherence and glycemic control using a large claims database. Methods Analyzed were 8805 patients with diabetes whose medication records for OHA were available for at least 1 year. Medication adherence was evaluated by the proportion of days covered (PDC). Multivariate logistic regression model was used to identify clinical variables significantly associated with non-adherence. Multiple regression analysis evaluated the relationship between PDC and HbA1c after adjusting for health-related behaviors. Results Mean PDC was 80.1% and 32.8% of patients were non-adherence. Logistic analysis indicated that older age and taking concomitant medications were significantly associated with adherence while skipping breakfast (odds ratio 0.66 [95% CI 0.57–0.76]), late-night eating (0.86 [0.75–0.98]), and current smoking (0.89 [0.80–0.99]) were significantly associated with non-adherence. Conclusions Skipping breakfast, late-night eating and current smoking were significantly associated with medication adherence, suggesting that clinicians pay attention to those health-related behaviors to achieve good medication adherence.

This network meta-analysis aimed to assess the current efficacy of decreasing the uric acid (UA) level with drugs to reduce mortality in patients with heart failure (HF). Electronic literature searches using EMBASE and MEDLINE of studies published from 1 Jan 1950 to 26 Dec 2019 were conducted for randomized controlled trials or non-randomized cohort studies that included at least one group of patients who took UA-lowering drugs and with a study outcome of all-cause mortality. A random-effects network meta-analysis was performed within a frequentist framework. Hierarchy of treatments was expressed as the surface under the cumulative ranking curve (SUCRA) value, which is in proportion to mean rank (best is 100%). Nine studies, which included seven different types of groups, were eligible for analysis. The “untreated uricemia” group in which patients had hyperuricemia but without treatment had a significantly higher risk of mortality than the “no uricemia” group in which patients had no hyperuricemia (relative risk (RR)(95% confidence interval (CI), 1.43 (1.08–1.89)). The “start-allo” group wherein patients started to take allopurinol did not have a significantly lower risk of mortality than the “untreated uricemia” group (RR (95% CI), 0.68 (0.45–1.01)). However, in the “start-allo” group the SUCRA value was comparable to that in the “no uricemia” group (SUCRA: 65.4% for “start-allo”; 64.1% for “no uricemia”). Results suggested that allopurinol therapy was not associated with a significantly improved prognosis in terms of mortality but could potentially counteract the adverse effects associated with longstanding hyperuricemia in HF patients.

Aim To examine the association between treatment-achieved HbA1c values and incidence of both coronary artery disease (CAD) and severe eye disease with different diabetes treatments. Methods Associations of treatment-achieved HbA1c were investigated in various treatment groups [diet only; insulin; sulphonylurea (SU) alone; SU with glinides; and antihyperglycaemic agents other than glinides, SU or insulin] taken from a nationwide claims database of 14,633 Japanese diabetes patients. Cox’s regression analysis examined risks over a 5.1-year follow-up. Results A significant linear trend was associated with HbA1c levels and CAD events in the diet-only group, and CAD risks were significantly higher in insulin and SU groups with HbA1c ≤ 7.0% and > 8.0% than in the diet-only group with HbA1c ≤ 7.0%. In contrast to CAD, a linear association was observed regardless of treatment modality between achieved HbA1c levels and risk of severe diabetic eye disease, but with no significant difference in eye disease risk between groups with HbA1c ≤ 7.0% and 7.1–8.0% in those treated with either SU alone, SU with glinides, or insulin. Conclusion These findings suggest that the relationship between treatment-achieved HbA1c and incidence of both CAD and severe diabetic eye disease differed according to treatment, based on a large-scale real-life database. More research is now needed to confirm these findings and to further investigate the underlying mechanisms.

Despite mounting evidence of the positive relationship between diabetes mellitus (DM) and heart failure (HF), the entire context of the magnitude of risk for HF in relation to DM remains insufficiently understood. The principal reason is because new‐onset HF (HF occurring in participants without a history of HF) and recurrent HF (HF re‐occurring in patients with a history of HF) are not discriminated. This meta‐analysis aims to comprehensively and separately assess the risk of new‐onset and recurrent HF depending on the presence or absence of DM. We systematically searched cohort studies that examined the relationship between DM and new‐onset or recurrent HF using EMBASE and MEDLINE (from 1 Jan 1950 to 28 Jul 2019). The risk ratio (RR) for HF in individuals with DM compared with those without DM was pooled with a random‐effects model. Seventy‐four and 38 eligible studies presented data on RRs for new‐onset and recurrent HF, respectively. For new‐onset HF, the pooled RR [95% confidence interval (CI)] of 69 studies that examined HF as a whole [i.e. combining HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF)] was 2.14 (1.96–2.34). The large between‐study heterogeneity (I2 = 99.7%, P

It is unclear whether genetic interactions are involved in the association between vegetable intake and reduced body mass index (BMI) or obesity. We conducted a comprehensive search for single nucleotide polymorphisms (SNPs) which are associated with the interaction between vegetable intake frequency and BMI or obesity. We performed a genome-wide association analysis to evaluate the genetic interactions between self-reported intake of vegetables such as carrot, broccoli, spinach, other green vegetables (green pepper and green beans), pumpkin, and cabbage with BMI and obesity, which is defined as a BMI ≥ 25.0 kg/m2 in the Japanese population (n = 12,225). The mean BMI and prevalence of obesity was 23.9 ± 3.4 kg/m2 and 32.3% in men and 22.1 ± 3.8 kg/m2 and 17.3% in in women, respectively. A significant interaction was observed between rs4445711 and frequency of carrot intake on BMI (p = 4.5 × 10−8). This interaction was slightly attenuated after adjustment for age, sex, alcohol intake, smoking, physical activity and the frequency of total vegetable intake (p = 2.1 × 10−7). A significant interaction was also observed between rs4445711 and frequency of carrot intake on obesity (p = 2.5 × 10−8). No significant interactions that were the same as the interaction between frequency of carrot intake and rs4445711 were observed between the intake frequency of broccoli, spinach, other green vegetables, pumpkin or cabbage and BMI or obesity. The frequency of carrot consumption is implicated in reducing BMI by the intermediary of rs4445711. This novel genetic association may provide new clues to clarify the association between vegetable intake and BMI or obesity.

Our purpose in the research was to clarify the impact of medication adherence to oral hypoglycemic agents during a 1-year period and subsequent glycemic control on the risk of micro- and macrovascular diseases.Examined was a nationwide claims database on 13,256 individuals with diabetic eye disease without requiring prior treatment, 7,862 without prior initiation of dialysis, 15,556 without prior coronary artery disease, 16,243 without prior cerebrovascular disease, and 19,386 without prior heart failure from 2008 to 2016 in Japan. Medication adherence was evaluated by the proportion of days covered. Patients were considered to have poor adherence if the proportion of days covered was80%. Multivariate Cox regression model identified risks of micro- and macrovascular diseases.In each group, mean age was 53 to 54 years, HbA1c was 7.1% to 7.2%, and median follow-up period was 4.6 to 5.1 years, and the percentage of poor adherence was approximately 30%. During the study period, 532 treatment-requiring diabetic eye disease, 75 dialysis, 389 coronary artery disease, 316 cerebrovascular disease, and 144 heart failure events occurred. Multivariate Cox regression model revealed that the hazard ratio (95% confidence interval) of dialysis in the poor adherence group was 2.04 (1.27-3.30) compared with the good adherence group. The hazard ratios in the poor adherence/poor glycemic control group were 3.34 (2.63-4.24) for treatment-requiring diabetic eye disease, 4.23 (2.17-8.26) for dialysis, 1.69 (1.23-2.31) for coronary artery disease, and 2.08 (1.25-3.48) for heart failure compared with the good adherence/good glycemic control group.Poor medication adherence was an independent risk factor for the initiation of dialysis, suggesting that clinicians must pay close attention to these patients.

We investigated the impact of medication adherence for a one-year period and subsequent glycemic control and their combinations on the risk of micro/macrovascular diseases among Japanese using nationwide claims data. Analyzed were 19,565 patients with diabetes whose medication records for oral hypoglycemic agents (OHAs) were available for at least 1 year without prior treatment-requiring diabetic eye disease (TRDED), initiation of dialysis (dialysis), coronary artery disease (CAD), or cerebrovascular disease (CVD), respectively (mean age 53y, HbA1c 7.2%). Medication adherence was evaluated by the proportion of days covered (PDC), and PDC Disclosure Y. Yaguchi: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. K. Fujihara: None. M. H. Yamada: None. Y. Matsubayashi: None. T. Yamada: None. M. Iwanaga: None. M. Kitazawa: None. M. Yamamoto: None. S. Kodama: None.

Heavy total alcohol consumption was reported to increase the risk of development and progression of diabetic retinopathy. However, differing from total alcohol consumption, whether the quantity of alcohol intake per occasion had harmful or beneficial effects related to severe eye diseases caused by diabetes remains unknown. To clarify this, we utilized ICD-10 and medical treatment codes from a nationwide claims database that finally included 21,392 men with type 2 diabetes (mean age 53 y, HbA1c 7.0%, mean follow-up period 4.3 y). During the study period, 425 patients developed vision-threatening treatment-required diabetic eye diseases (TRDED) (4.6/1000 person-years). Multivariate Cox analysis demonstrated that a large quantity of alcohol per occasion defined as ≥3 drinks per occasion was positively associated with future occurrence of TRDED. One drink was defined as a standard Japanese drink with a volume equivalent to 23 g ethanol. Hazard ratio in patients drinking large amounts of alcohol per occasion for incident TRDED was 4.49 (95% confidence interval, 1.98-10.19) compared with the reference group (≤1 drink per occasion) after adjusting for covariates including total alcohol consumption. This finding demonstrated that a large quantity of alcohol per occasion had a significant association with future vision-threatening retinopathy in men with type 2 diabetes. The mechanism of this finding with regard to severe retinopathy awaits further research. Disclosure M. Yamamoto: None. T. Yamada: None. S. Kodama: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. K. Fujihara: None. Y. Yaguchi: None. T. Osawa: None. M. Kaneko: None. M. Kitazawa: None. T. Sato: None. M. H. Yamada: None. Y. Matsubayashi: None.

Background: Simple physical fitness test can be a useful potential predictor of type 2 diabetes (T2DM). We examined the association between performances on simple physical fitness tests and the incidence of T2DM. Methods: This longitudinal study was conducted in 21,802 nondiabetic Japanese (6,649 women) aged 20 to 92 years, who underwent all physical fitness tests at baseline (April 2001 to March 2002). From April 2001 to March 2008, physical fitness tests, including grip strength, vertical jump, single-leg balance with eyes closed, forward bending, whole-body reaction time, and supine legs-up, were performed every year. Participants had physical fitness tests at least two times during the period. T2DM was also annually determined based on fasting blood glucose, glycated hemoglobin, and self-reported diabetes during the period. Discrete-time logit models were used to examine the influence of the serial level of each physical fitness test on the incidence of T2DM. Results: During the entire study period, 972 participants developed diabetes. Lower relative grip strength (grip strength/body weight) and single-leg balance performance were associated with a higher incidence of T2DM. For relative grip strength, as compared with the fourth quartile group, the odds ratios for other groups ranged from 1.16 to 1.56 (P for trend < 0.001). For single-leg balance, the odds ratios ranged from 1.03 to 1.49 (P for trend < 0.001). Conclusion: The performance of a simple single-leg balance test as well as that of a grip strength test were negatively associated with the risk of T2DM among Japanese.

Giant cell arteritis (GCA) is a type of large vessel vasculitis, and it involves the aorta, large vessels and terminal branches of the external carotid artery, especially the temporal artery. Temporal artery biopsy is a simple tool for the diagnosis of vasculitis, however, the histopathological findings do not always differentiate between the small-vessel vasculitis and GCA. We report the case of 72-year-old male who initially had a clinical diagnosis of GCA, then in the course of treatment, diagnostic histopathological approach revealed the necrotizing vasculitis with bronchocentric granulomatosis in the inflammatory nodule of the lung. The manifestations of patients with systemic vasculitis represent the disorders of multiple organ systems thus are diverse and may vary through the course of the disease. Presentation of unexpected features such as insufficient response to antibiotics, sinusitis, runny nose, discomfort of frontal region or pachymeningitis which anticipates re-evaluation of systemic vasculitis that may lead us to an appropriate diagnosis and the treatment.

Background Strong eosinophil infiltration in chronic rhinosinusitis with nasal polyp (CRSwNP) is highly associated with recalcitrance and higher nasal polyp recurrence rate after surgery. The prevalence of eosinophilic CRSwNP (ECRS) is increasing in Asian countries including Japan. Benralizumab is a humanized anti-IL-5R alpha monoclonal antibody that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity. Objective To assess the efficacy and safety of benralizumab in patients with ECRS. Methods This phase II, randomized, double-blind, placebo-controlled study was conducted in Japan. Patients were randomized 1:2:2 to placebo, a single administration of benralizumab 30 mg, or benralizumab 30 mg every 4 weeks (q4w) for a total of three doses. The primary endpoint was the change in nasal polyp score from baseline at Week 12. Results Overall, 56 patients were enrolled (placebo, n = 11; benralizumab single dose, n = 22; benralizumab q4w, n = 23). Although the mean total nasal polyp score began to decrease after the initiation of benralizumab treatment, there were no statistically significant differences in change in nasal polyp score from baseline at Week 12 between benralizumab and placebo (placebo, −0.5 ± 0.8; benralizumab single, −0.3 ± 0.8; benralizumab q4w, −0.5 ± 1.5). Post-hoc analysis showed that the administration of benralizumab decreased nasal polyp scores ≥2 points in 42.2% of ECRS patients and that patients with high blood eosinophil levels had a greater tendency to respond to benralizumab treatment. The safety profile was similar to that in previous studies and no unexpected adverse events were noted. Conclusion Although benralizumab did not meet the primary efficacy endpoint, reductions of nasal polyp scores were seen in the benralizumab group compared with the placebo group over the whole study period, especially in patients with high levels of blood eosinophils.

Purpose To evaluate the accuracy of various claims-based definitions of diabetes-related complications (coronary artery disease [CAD], heart failure, cerebrovascular disease and dialysis). Methods We evaluated data on 1379 inpatients who received care at the Niigata University Medical & Dental Hospital in September 2018. Manual electronic medical chart reviews were conducted for all patients with regard to diabetes-related complications and were used as the gold standard. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each claims-based definition associated with diabetes-related complications based on Diagnosis Procedure Combination (DPC), International Classification of Diseases, Tenth Revision (ICD-10) codes, procedure codes and medication codes were calculated. Results DPC-based definitions had higher sensitivity, specificity, and PPV than ICD-10 code definitions for CAD and cerebrovascular disease, with sensitivity of 0.963-1.000 and 0.905-0.952, specificity of 1.000 and 1.000, and PPV of 1.000 and 1.000, respectively. Sensitivity, specificity, and PPV were high using procedure codes for CAD and dialysis, with sensitivity of 0.963 and 1.000, specificity of 1.000 and 1.000, and PPV of 1.000 and 1.000, respectively. DPC and/or ICD-10 codes + medication were better for heart failure than the ICD-10 code definition, with sensitivity of 0.933, specificity of 1.000, and PPV of 1.000. The PPVs were lower than 60% for all diabetes-related complications using ICD-10 codes only. Conclusion The DPC-based definitions for CAD and cerebrovascular disease, procedure codes for CAD and dialysis, and DPC or ICD-10 codes with medication codes for heart failure could accurately identify these diabetes-related complications from claims databases.

Background Machine learning (ML) algorithms have been widely introduced to diabetes research including those for the identification of hypoglycemia. Objective The objective of this meta-analysis is to assess the current ability of ML algorithms to detect hypoglycemia (ie, alert to hypoglycemia coinciding with its symptoms) or predict hypoglycemia (ie, alert to hypoglycemia before its symptoms have occurred). Methods Electronic literature searches (from January 1, 1950, to September 14, 2020) were conducted using the Dialog platform that covers 96 databases of peer-reviewed literature. Included studies had to train the ML algorithm in order to build a model to detect or predict hypoglycemia and test its performance. The set of 2 × 2 data (ie, number of true positives, false positives, true negatives, and false negatives) was pooled with a hierarchical summary receiver operating characteristic model. Results A total of 33 studies (14 studies for detecting hypoglycemia and 19 studies for predicting hypoglycemia) were eligible. For detection of hypoglycemia, pooled estimates (95% CI) of sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were 0.79 (0.75-0.83), 0.80 (0.64-0.91), 8.05 (4.79-13.51), and 0.18 (0.12-0.27), respectively. For prediction of hypoglycemia, pooled estimates (95% CI) were 0.80 (0.72-0.86) for sensitivity, 0.92 (0.87-0.96) for specificity, 10.42 (5.82-18.65) for PLR, and 0.22 (0.15-0.31) for NLR. Conclusions Current ML algorithms have insufficient ability to detect ongoing hypoglycemia and considerate ability to predict impeding hypoglycemia in patients with diabetes mellitus using hypoglycemic drugs with regard to diagnostic tests in accordance with the Users’ Guide to Medical Literature (PLR should be ≥5 and NLR should be ≤0.2 for moderate reliability). However, it should be emphasized that the clinical applicability of these ML algorithms should be evaluated according to patients’ risk profiles such as for hypoglycemia and its associated complications (eg, arrhythmia, neuroglycopenia) as well as the average ability of the ML algorithms. Continued research is required to develop more accurate ML algorithms than those that currently exist and to enhance the feasibility of applying ML in clinical settings. Trial Registration PROSPERO International Prospective Register of Systematic Reviews CRD42020163682; http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42020163682

To determine associations between severity of hypertension and risk of starting dialysis in the presence or absence of diabetes mellitus (DM). A nationwide database with claims data on 258 874 people with and without DM aged 19-72 years in Japan was used to elucidate the impact of severity of hypertension on starting dialysis. Initiation of dialysis was determined from claims using International Classification of Diseases-10 codes and medical procedures. Using multivariate Cox modeling, we investigated the severity of hypertension to predict the initiation of dialysis with and without DM. Hypertension was significantly associated with the initiation of dialysis regardless of DM. The incidence of starting dialysis in those with systolic blood pressure (SBP) ≤119 mm Hg and DM (DM+) was almost the same as in those with SBP ≥150 mm Hg and absence of DM (DM−). In comparison with SBP ≤119 mm Hg, SBP ≥150 mm Hg significantly increased the risk of the initiation of dialysis about 2.5 times regardless of DM+ or DM−. Compared with DM− and SBP ≤119 mm Hg, the HR for DM+ and SBP ≥150 mm Hg was 6.88 (95% CI 3.66 to 12.9). Although the risks of hypertension differed only slightly regardless of the presence or absence of DM, risks for starting dialysis with DM+ and SBP ≤119 mm Hg were equivalent to DM− and SBP ≥150 mm Hg, indicating more strict blood pressure interventions in DM+ are needed to avoid dialysis. Future studies are required to clarify the cut-off SBP level to avoid initiation of dialysis considering the risks of strict control of blood pressure.

OBJECTIVE To determine associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with new-onset coronary artery disease (CAD) or cerebrovascular disease (CVD) according to glucose status. RESEARCH DESIGN AND METHODS Examined was a nationwide claims database from 2008 to 2016 on 593,196 individuals. A Cox proportional hazards model identified risks of CAD and CVD events among five levels of SBP and DBP. RESULTS During the study period 2,240 CAD and 3,207 CVD events occurred. Compared with SBP ≤119 mmHg, which was the lowest quintile of SBP, hazard ratios (95% CI) for CAD/CVD in the 4 higher quintiles (120–129, 130–139, 140–149, ≥150 mmHg) gradually increased from 2.10 (1.73–2.56)/1.46 (1.27–1.68) in quintile 2 to 3.21 (2.37–4.34)/4.76 (3.94–5.75) in quintile 5 for normoglycemia, from 1.39 (1.14–1.69)/1.70 (1.44–2.01) in quintile 2 to 2.52 (1.95–3.26)/4.12 (3.38–5.02) in quintile 5 for borderline glycemia, and from 1.50 (1.19–1.90)/1.72 (1.31–2.26) in quintile 2 to 2.52 (1.95–3.26)/3.54 (2.66–4.70) in quintile 5 for diabetes. A similar trend was observed for DBP across 4 quintiles (75–79, 80–84, 85–89, and ≥90 mmHg) compared with ≥74 mmHg, which was the lowest quintile. CONCLUSIONS Results indicated that cardiovascular risks gradually increased with increases in SBP and DBP regardless of the presence of and degree of a glucose abnormality. Further interventional trials are required to apply findings from this cohort study to clinical practice.

We examined whether the machine learning approach could be used as support for decision-making by general physicians as to whether to use insulin as an initial therapy for patients with type 2 diabetes. Prescription data on different antidiabetic agents from December 2009 to March 2015 from diabetes specialists’ patient registries were used to compare the machine learning decision of initial insulin use to that of general physicians. Gold standard was defined as consensus, that is, 80% agreement among nine diabetes specialists based on patients’ information. Twenty-two general physicians chose the most suitable medication according to the patients’ information. Analyzed were data on 4,860 patients who received initial monotherapy with either insulin (293 patients) or non-insulin (4,567 patients) and had laboratory data. Accuracy was calculated by 5-fold cross validation in machine learning. The average predictive values of initial insulin use by machine learning were 0.40, 0.50 and 0.82, respectively, for under-sampling ratios of 1:2, 1:4 and 1:8. General physicians achieved a mean accuracy for initial insulin use of 51%. The overall accuracy was 43%, 57% and 86% for under-sampling ratios of 1:2, 1:4 and 1:8. The difference in the accuracy between general physicians and machine learning in the under-sampling ratio of 1:8 was significant (P In conclusion, accuracy of machine learning with the sampling ratio of 1:8 was higher compared with that of general physicians in initial insulin use defined by diabetes specialists’ choice as the gold standard. Assistance by machine learning may be beneficial to any general physician in deciding upon initial insulin usage. Disclosure K. Fujihara: None. M.H. Yamada: None. Y. Matsubayashi: None. M. Yamamoto: None. T. Iizuka: None. K. Miyamura: None. Y. Hasegawa: None. T. Yamazaki: None. S. Kodama: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Funding Japan Society for the Promotion of Science (18K17897)

Machine learning (ML) methods receive increasing attention for diabetes risk assessment. This meta-analysis quantitatively assessed the predictive ability of ML algorithms for incident T2DM. Electronic literature searches were done using MEDLINE and EMBASE for longitudinal studies whereby an index test was a model constructed by ML algorithms for predicting incident T2DM. Reference standard was a blood test or physicians’ diagnosis confirming T2DM. The model was restricted to algorithms that required the aid of ML (e.g., neural network, support vector machine, etc.). The 2x2 contingency data (i.e., true-positive, false-positive, false-negative, and true-negative) were pooled with a hierarchical summary receiver operating characteristic model. Pooled sensitivity and specificity (95% confidence interval (CI)) of 8 eligible studies were 0.70 (0.66-0.74) and 0.78 (0.69-0.85), respectively. (Figure) Positive likelihood ratio (PLR) calculated as sensitivity/(1-specificity) and negative likelihood ratio (NLR) calculated as (1-sensitivity)/specificity were 3.25 (95%CI, 2.25-4.58) and 0.38 (95% CI, 0.34-0.43), respectively. We conclude that existing prediction models are not yet satisfactory considering that PLR>5 moderately increases the probability of a disease given a positive test and NLR Disclosure S. Kodama: None. T. Sato: None. M. Yamamoto: None. H. Ishiguro: None. M. Iwanaga: None. K. Fujihara: None. T. Yamada: None. K. Kato: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.

Some plasma metabolites in the urea cycle were reportedly associated with DKD, although results were inconsistent among studies. Also, few studies examined the association between urea cycle metabolites and DKD in community dwellers. To address this, we used the metabolite database from the Tsuruoka Metabolomics Cohort Study, which had global metabolomics in Japan, using capillary electrophoresis-mass spectrometry. Among 10,933 participants, cross-sectionally analyzed were 1,005 who had diabetes mellitus (DM) defined by HbA1c ≥6.5%, and/or fasting blood glucose ≥126 mg/dl and/or antidiabetic drug use. Of these 231 had DKD, which was defined by eGFR Disclosure M. Yamamoto: None. S. Harada: None. T. Okamura: None. K. Fujihara: None. Y. Yaguchi: None. T. Komatsu: None. T. Sato: None. M. Kitazawa: None. M.H. Yamada: None. M. Kaneko: None. T. Osawa: None. Y. Matsubayashi: None. T. Yamada: None. S. Kodama: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. T. Takebayashi: None.

Declining healthy life expectancy due to functional disability is relevant and urgent not only because of its association with decreased quality of life but also for its enormous socioeconomic impact. Thus, we analyzed a population-based retrospective cohort study including 9,673 community dwelling Japanese adults (4,420, men) aged 39-98 years in 2012-2017. Functional disability was defined as a condition meeting Japan’s new long-term care insurance certification requirements for the need of assistance in the activities of daily living whether by caregivers or assistive devices. Cox proportional hazards regression model identified variables related to functional disability. Median follow-up was 3.7 years. During the study period, 165 disabilities occurred in the overall study population. Multivariate analysis showed that diabetes (hazard ratio [HR] 1.74 (95% CI: 1.12-2.68)), no physical activity habit (HR 1.83 (1.27-2.65)), and low BMI category (18.5 kg/m2 >) (HR 1.63 (1.02-2.63)) presented increased risks for disability. The prevalence ratio of 0, 1, 2, 3 and 4 conditions (diabetes, hypertension, dyslipidemia, and physical activity habits) was 12.8%, 40.0%, 32.6%, 12.9 and 1.7%, respectively. HR for disability increased with the number of risk factors (HR of individuals with 1, 2, 3 and 4 conditions, 1.34 (0.71-2.52), 1.95 (1.04-3.63), 2.11 (1.07-4.15), and 3.96 (1.59-9.99) vs. individuals with none of those conditions as a ref.). HR for disability among diabetes patients with and without a physical activity habit was 1.68 (0.70-4.04) and 3.19 (1.79-5.70), respectively, compared to individuals without diabetes with a physical activity habit. This shows that the combination of diabetes and lack of habitual physical activity is predictive of functional disability in Japanese. Habitual physical activity attenuates the risk of functional disability in patients with diabetes. Disclosure K. Fujihara: None. M.H. Yamada: None. Y. Matsubayashi: None. M. Kitazawa: None. M. Kaneko: None. M. Yamamoto: None. Y. Yaguchi: None. T. Yahiro: None. S. Kodama: None. K. Kato: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Funding Japan Society for the Promotion of Science (18K17897)

Low serum AMY values were previously reported to be associated with incident T2DM. We further investigated that association in detail by showing the combined effects of chronological changes in AMY and baseline AMY as well as results of stratified analyses of baseline age and HbA1c. Analyzed were 5306 individuals who had health examinations yearly for 7 y. We monitored changes in AMY values between baseline1 (first visit) and baseline2 (2 y later). Multivariate Cox analysis was conducted to evaluate the impacts of baseline2 AMY and change in AMY on incident T2DM in consideration of age and HbA1c. During the 5-y follow-up, T2DM occurred in 716 patients. Both low baseline2 AMY and decrease in AMY were independently associated with the development of T2DM. Compared with those whose baseline2 AMY ≥57 (Quintiles (Q) 2-5) and changes in AMY ≥90.4 (Q 2-5), those whose baseline2 AMY ≤56 (Q1) and changes in AMY ≤90.3 (Q1) had a significantly increased risk for T2DM (HR 1.60 [1.22-2.09]). Stratified analyses by age and baseline HbA1c levels showed that the increased risk for T2DM due to low baseline2 AMY or its change occurred only among those These findings imply the clinical relevance of using AMY values and their chronological changes over time for evaluation of T2DM risk among individuals who are relatively young or have low HbA1c. Disclosure I. Ikeda: None. K. Fujihara: None. I. Risa: None. M.H. Yamada: None. R. Nedachi: None. M. Hatta: None. S. Kodama: None. Y. Mori: None. Y. Matsubayashi: None. Y. Arase: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. R. Yamamoto-Honda: None.

Background: Grip strength reflects systemic muscle strength and mass and is reportedly associated with various metabolic variables. However, its prognostic association with dyslipidemia is unknown. We examined the association of grip strength and other physical fitness markers with the incidence of dyslipidemia among Japanese adults. Methods: A total of 16,149 Japanese (6,208 women) individuals aged 20–92 years who underwent a physical fitness test between April 2001 and March 2002 were included in this cohort study. Grip strength, vertical jump, single-leg balance with eyes closed, forward bending, and whole-body reaction time were evaluated at baseline. Dyslipidemia was annually determined based on fasting serum lipid profiles and self-reported dyslipidemia from April 2001 to March 2008. Results: During the follow-up period, 4,458 (44.9%) men and 2,461 (39.6%) women developed dyslipidemia. A higher relative grip strength (grip strength/body mass index) was associated with a lower incidence of dyslipidemia among both men and women (P for trend

Summary Background & aims High intake of fruit and vegetables is recommended for cardiovascular health. However, there have been persistent beliefs that fruits having high concentrations of fructose elevate the level of triglycerides (TG) in blood unlike vegetables. This meta-analysis aims to clarify the relationship between fruit intake and TG or hypertriglyceridemia. Methods Electronic literature searches were conducted for observational studies that investigated the relationship between fruit intake and hypertriglyceridemia or intervention studies that investigated the effect of increasing fruit intake on TG. Each effect size was pooled with an inverse-variance method. Results Five cross-sectional studies and only 2 intervention studies were eligible. The pooled odds ratio (OR) (95% confidence interval (CI)) of the 5 cross-sectional studies for the highest vs. the lowest fruit intake category was 0.79 (0.72–0.87). In these studies, the pooled OR for the highest vs. the lowest vegetable intake category was not significant (OR = 0.92; 95% CI, (0.82–1.03)). A linear dose–response association was observed between increases in fruit intake and ORs for hypertriglyceridemia; the OR (95% CI) for an incrementally increased intake of fruit by 1 serving/day was 0.91 (0.84–0.98). Conclusion This meta-analysis suggests that high intake of fruit but not vegetables is inversely associated with hypertriglyceridemia. More trials are needed to clarify whether increasing fruit intake would reduce the level of TG and/or incident hypertriglyceridemia.

Background Bariatric surgery leads to a higher remission rate for type 2 diabetes mellitus than non-surgical treatment. However, it remains unsolved which surgical procedure is the most efficacious. This network meta-analysis aimed to rank surgical procedures in terms of diabetes remission. Methods and findings We electronically searched for randomized controlled trials in which at least one surgical treatment was included among multiple arms and the diabetes remission rate was included in study outcomes. A random-effects network meta-analysis was performed within a frequentist framework. The hierarchy of treatments was expressed as the surface under the cumulative ranking curve value. Results of the analysis of 25 eligible randomized controlled trials that covered non-surgical treatments and eight surgical procedures (biliopancreatic diversion [BPD], BPD with duodenal switch, Roux-en Y gastric bypass, mini gastric bypass [mini-GBP], laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy, greater curvature plication and duodenal-jejunal bypass) showed that BPD and mini-GBP had the highest surface under the cumulative ranking curve values among the eight surgical treatments. Conclusion Current network meta-analysis indicated that BPD or mini-GBP achieved higher diabetes remission rates than the other procedures. However, the result needs to be interpreted with caution considering that these procedures were in the minority of bariatric surgeries.

AIM Hepatic insulin clearance (HIC) is important in regulating plasma insulin levels. Diminished HIC causes inappropriate hyperinsulinaemia, and both obesity and fatty liver (FL), which are known to decrease HIC, can be found either together in the same patient or on their own. The mechanism by which obesity reduces HIC is presumed to be mediated by FL. However, few reports have examined the role of FL in the relationship between obesity and HIC in type 2 diabetes (T2D) patients. Therefore, our study investigated the association of HIC with clinical factors, including insulin sensitivity indices, focusing on the presence or absence of FL and obesity in T2D patients. METHOD Baseline data from 419 patients with T2D (279 men, 140 women; mean age: 57.6 years; body mass index: 25.5kg/m2) controlled by diet and exercise were analyzed. HIC was calculated from the ratio of fasting c-peptide to fasting insulin levels (HICCIR). Correlation analyses between HICCIR and clinical variables were performed using Pearson's product-moment correlation coefficients and single regression analysis in all participants and in those with obesity and FL either alone or in combination. RESULTS HICCIR was significantly correlated with whole-body insulin sensitivity indices and influenced by FL, but only in the FL group was obesity independently influenced HIC level. HICCIR decreased in those with both FL and obesity compared with those with only one such complication. CONCLUSION HICCIR may be used to evaluate whole-body insulin sensitivity in T2D. Also, compared with obesity, the influence of FL strongly contributed to a reduced HIC. TRIAL REGISTRATION NUMBER These trials were registered by the Japan Pharmaceutical Information Centre clinical trials information (JapicCTI) as 101349 and 101351.

Many epidemiological studies have assessed the genetic risk of having undiagnosed or of developing type 2 diabetes mellitus (T2DM) using several single nucleotide polymorphisms (SNPs) based on findings of genome-wide association studies (GWAS). However, the quantitative association of cumulative risk alleles (RAs) of such SNPs with T2DM risk has been unclear. The aim of this meta-analysis is to review the strength of the association between cumulative RAs and T2DM risk. Systematic literature searches were conducted for cross-sectional or longitudinal studies that examined odds ratios (ORs) for T2DM in relation to genetic profiles. Logarithm of the estimated OR (log OR) of T2DM for 1 increment in RAs carried (1-ΔRA) in each study was pooled using a random-effects model. There were 46 eligible studies that included 74,880 cases among 249,365 participants. In 32 studies with a cross-sectional design, the pooled OR for T2DM morbidity for 1-ΔRA was 1.16 (95% confidence interval [CI], 1.13–1.19). In 15 studies that had a longitudinal design, the OR for incident T2DM was 1.10 (95% CI, 1.08–1.13). There was large heterogeneity in the magnitude of log OR (P < 0.001 for both cross-sectional studies and longitudinal studies). The top 10 commonly used genes significantly explained the variance in the log OR (P = 0.04 for cross-sectional studies; P = 0.006 for longitudinal studies). The current meta-analysis indicated that carrying 1-ΔRA in T2DM-associated SNPs was associated with a modest risk of prevalent or incident T2DM, although the heterogeneity in the used genes among studies requires us to interpret the results with caution.

Objective This study aimed to examine the impact of obesity, as defined by body mass index (BMI), and a metabolically unhealthy phenotype on the development of coronary artery disease (CAD) according to glucose tolerance status. Methods This population-based retrospective cohort study included 123,746 Japanese men aged 18–72years (normal glucose tolerance: 72,047; prediabetes: 39,633; diabetes: 12,066). Obesity was defined as a BMI≥25kg/m 2 . Metabolically unhealthy individuals were defined as those with one or more of the following conditions: hypertension, hypertriglyceridaemia and/or low HDL cholesterol. A Cox proportional hazards regression model identified variables related to CAD incidence. Results The prevalences of obese subjects with normal glucose tolerance, prediabetes and diabetes were 21%, 34% and 53%, whereas those for metabolically unhealthy people were 43%, 60% and 79%, respectively. Multivariate analysis showed that a metabolically unhealthy phenotype increases hazard ratios (HRs) for CAD compared with a metabolically healthy phenotype, regardless of glucose tolerance status (normal glucose tolerance: 1.98, 95% CI: 1.32–2.95; prediabetes: 2.91, 95% CI: 1.85–4.55; diabetes: 1.90, 95% CI: 1.18–3.06). HRs for CAD among metabolically unhealthy non-obese diabetes patients and obese diabetes patients with a metabolically unhealthy status were 6.14 (95% CI: 3.94–9.56) and 7.86 (95% CI: 5.21–11.9), respectively, compared with non-obese subjects with normal glucose tolerance and without a metabolically unhealthy status. Conclusion A metabolically unhealthy state can associate with CAD independently of obesity across all glucose tolerance stages. Clinicians may need to consider those with at least one or more conditions indicating a metabolically unhealthy state as being at high risk for CAD regardless of glucose tolerance status.

Olfactory neuroblastoma (ONB) is a relatively rare nasal or paranasal malignant tumor. This tumor is rarely accompanied by paraneoplastic syndromes such as syndrome of inappropriate antidiuretic hormone secretion (SIADH). Here, we report a 31-year-old female with histologically confirmed ONB who had been diagnosed with SIADH three years prior. She was treated with surgery followed by concurrent chemoradiotherapy. SIADH resolved immediately after surgical tumor resection. Immunohistochemically, both biopsy and resected specimens from the nasal cavity had been negative for ADH. Although extremely rare, ONB may be associated with SIADH, and the possibility of this cancer should be taken into account during the follow-up of idiopathic SIADH.

Aims To examine the impact of glucose tolerance status on the development of coronary artery disease (CAD) in working-age men in Japan. Methods This population-based retrospective cohort study included 111,621 men aged 31–60 years [63,558 with normal glucose tolerance (NGT); 37,126 with prediabetes; 10,937 with diabetes]. The Cox proportional-hazards regression model was used to identify variables related to the incidence of CAD. Results Multivariate analysis showed that, compared with NGT, diabetes increased the risk of CAD by 17.3 times (95% CI: 6.36–47.0) at ages 31–40 years, by 2.74 times (95% CI: 1.85–4.05) at ages 41–50 years and by 2.47 times (95% CI: 1.69–3.59) at ages 51–60 years. The HRs for CAD in men with diabetes aged 31–40 equaled that of men with NGT aged 51–60 [18.2 (7.15–46.4) and 19.4 (8.28–45.4), respectively]. Conclusion The impact of diabetes on CAD was markedly greater in men aged 31–40 years compared with those aged 41–60 years.

Objective Acute otitis media (AOM) is one of the most common infectious diseases in children. Nontypeable Haemophilus influenzae (NTHi) is Gram-negative bacteria that are considered major pathogens of AOM and respiratory tract infections. In this study, we used monophosphoryl lipid A (MPL), a toll-like receptor (TLR) 4 agonist, as an adjuvant to induce mucosal immune responses against NTHi to enhance bacterial clearance from the nasopharynx. Methods Mice were administered 10 μg outer membrane protein (OMP) from NTHi and 0, 10, or 20 μg MPL intranasally once a week for 3 weeks. Control mice were administered phosphate-buffered saline alone. After immunization, these mice were challenged with NTHi. At 6 and 12 h after bacterial challenge, the mice were killed and nasal washes and sera were collected. The numbers of NTHi- and OMP-specific antibodies were quantified by enzyme-linked immunosorbent assay. Results The MPL 10 and 20 μg group produced a significant reduction in the number of bacteria recovered from the nasopharynx at 12 h after bacterial challenge compared to the control group. OMP-specific IgA titers were also augmented in the MPL groups compared to the control and OMP groups. Conclusion MPL is suitable for eliciting effective mucosal immune responses against NTHi in the nasopharynx. These results demonstrate the possibility of an adjuvant that involves stimulation of the innate immune system by TLR4 agonists such as MPL for mucosal vaccination.

Solitary fibrous tumor (SFT) is an uncommon neoplasm that usually arises from the pleura. Recently, SFTs have been reported in the head and neck region located in subsites such as the orbit. SFTs of the lacrimal sac are extremely rare, with only six cases reported in the English literature. We describe a SFT arising from the right lacrimal sac and extending along the nasolacrimal duct into the nasal cavity. Although, the tumor could not be removed by endoscopic-modified medial maxillectomy (EMMM) alone, combined approach with EMMM and a small external incision achieved the complete removal of the tumor. The patient has remained disease-free 24 months after surgery.

Aims/Introduction The present meta-analysis aimed to clarify the association of unstable bodyweight with the risk of type 2 diabetes mellitus, an association that has been controversial among longitudinal studies., Materials and Methods An electronic literature search using EMBASE and MEDLINE was followed up to 31 August 2016. The relative risks (RRs) of type 2 diabetes mellitus in individuals with unstable bodyweight were pooled using the inverse variance method., Results Eight studies were eligible for the meta-analysis. The median duration of measurements of weight change and follow-up years for ascertaining type 2 diabetes mellitus were 13.5 and 9.4 years, respectively. The pooled RR for the least vs most stable category was 1.33 (95% confidence interval 1.12–1.57). Between-study heterogeneity was statistically significant (P = 0.048). Whether type 2 diabetes mellitus was ascertained by blood testing explained 66.0% of the variance in the logarithm of RR (P = 0.02). In three studies in which blood testing was carried out, type 2 diabetes mellitus risk was not significant (RR 1.06, 95% confidence interval 0.91–1.25). Furthermore, publication bias that inflated type 2 diabetes mellitus risk was statistically detected by Egger's test (P = 0.09)., Conclusions Unstable bodyweight might be modestly associated with the elevated risk of type 2 diabetes mellitus; although serious biases, such as diagnostic suspicion bias and publication bias, made it difficult to assess this association.

Pediatric obesity is associated with clustered cardiometabolic risk and the future incidence of diabetes. However, few studies have determined the effect of pediatric obesity in Asia, where obesity is less common than in Western countries. Thus, we clarified whether metabolic risk factors are associated with weight status including slight overweight and underweight among Japanese adolescents. We performed a cross-sectional analysis of 2241 Japanese adolescents (1180 boys) aged 13-14 years whose height, weight, HbA1c, blood pressure (BP), and serum lipids were measured. Participants were classified as underweight, normal weight, slightly overweight, overweight, or obese according to both the universal and Asian cutoffs of the International Obesity Task Force, which correspond to adult BMI cutoffs. The clustered cardiometabolic risk (Z-CMR) was estimated by summing standardized sex-specific Z scores of HbA1c, mean arterial pressure (MAP), and non-high-density lipoprotein cholesterol (non-HDL-C). Linear regression analysis showed that MAP (sex-specific Z score), non-HDL-C (sex-specific Z score), and Z-CMR were higher in the slightly overweight, overweight, and obese groups than in the normal weight group after adjusting for confounders. Compared with the normal weight group, the slightly overweight, overweight, and obese groups had significantly higher odds ratios (ORs) for high BP [OR = 1.38 (95% CI, 1.03-1.85); OR = 2.63 (1.77-3.91); and OR = 2.39 (1.57-3.64), respectively]. Compared with the normal weight group, underweight boys, but not girls, had a significantly lower OR for high Z-CMR [OR = 0.20 (0.05-0.84)]. Our results indicated that adolescents classified as slightly overweight had higher levels of BP, serum lipids (but not HbA1c), and clustered cardiometabolic risk than those classified as normal weight. This observation demonstrated that significant associations between weight status and cardiometabolic risk factors could be seen during adolescence even in East Asia. Disclosure S.Y. Morikawa: None. K. Fujihara: None. D. Ishii: None. R. Nedachi: None. M. Ishizawa: None. H. Ishiguro: None. Y. Matsubayashi: None. T. Yamada: None. S. Kodama: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.

Although both a glucose metabolism abnormality and prior cerebrovascular disease (CVD) are major predictors of CVD, few studies have compared their impact on a subsequent CVD event. Also, few studies evaluated risk of prediabetes separately from nondiabetic categories. Thus, the impact of diabetes mellitus (DM) on subsequent CVD compared to normal glucose tolerance (NGT) could have been underestimated. We analyzed a nationwide claims-based database of 290,865 participants in 2008-14. Participants were classified as having NGT, prediabetes or DM based on fasting plasma glucose, HbA1c and use of antihypoglycemic agents (185,648 with NGT; 87,867 with prediabetes; 17,350 with DM). Participants were also classified as with or without prior CVD based on ICD-10 and questionnaires (1,944 with prior CVD; 288,921 without prior CVD). Cox regression model showed that prediabetes and DM confers about 1.1- and 1.4-fold excess risk for CVD, respectively, compared to NGT without prior CVD. Prediabetes and DM does not increase risk for CVD compared to NGT with prior CVD (Table). Prior CVD confers a 4-7-fold excess risk for CVD regardless of glucose tolerance status. Hazard ratio of CVD in NGT with prior CVD was 4 times higher than in DM without prior CVD. This implies that prediabetes and DM increase CVD only in those without prior CVD. Prior CVD confers a higher risk for subsequent CVD regardless of glucose tolerance status. Disclosure D. Yanagisawa: None. K. Fujihara: None. T. Osawa: None. M. Kitazawa: None. M. Yamamoto: None. Y. Matsubayashi: None. N. Yamanaka: None. S. Kodama: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.

Background Evidence of the role of systolic blood pressure (SBP) in development of severe diabetic retinopathy is not strong, although the adverse effect of low diastolic blood pressure has been a partial explanation. We assessed the predictive ability of incident severe diabetic retinopathy between pulse pressure (PP) which considers both SBP and diastolic blood pressure, compared with SBP. Methods and Results Eligible patients (12 242, 83% men) aged 19 to 72 years from a nationwide claims database were analyzed for a median observational 4.8‐year period. Severe diabetic retinopathy was defined as vision‐threatening treatment‐required diabetic eye diseases. Multivariate Cox regression analysis revealed that hazard ratios (95% CI) of treatment‐required diabetic eye diseases for 1 increment of standard deviation and the top tertile compared with the bottom tertile were 1.39 (1.21–1.60) and 1.72 (1.17–2.51), respectively, for PP and 1.22 (1.05–1.41) and 1.43 (0.97–2.11), respectively, for SBP adjusted for age, sex, body mass index, hemoglobin A1c, fasting plasma glucose, lipids, and smoking status. In a model with SBP and PP simultaneously as covariates, the hazard ratios of only PP (hazard ratios [95% CI], 1.57 [1.26–1.96]) but not SBP (0.85 [0.68–1.07]) were statistically significant. Delong test revealed a significant difference in the area under the receiver operating characteristic curve between PP and SBP (area under the receiver operating characteristic curve [95% CI], 0.58 [0.54–0.63] versus 0.54 [0.50–0.59]; P=0.03). The strongest predictor remained as hemoglobin A1c (area under the receiver operating characteristic curve [95% CI], 0.80 [0.77–0.84]). Conclusions After excluding the significant impact of glycemic control, PP in comparison with SBP is a better predictor of severe diabetic retinopathy, suggesting a role of diastolic blood pressure and arterial stiffness in pathology., See Editorial Dart

Highlights • Extracranial meningiomas are rare, of a secondary type, and of intracranial origin. • We describe a case of sphenoid ridge meningioma extending into the sphenoid sinus. • The tumor was resected by staged transcranial and endoscopic endonasal resection. • A transsphenoidal and transpterygoid approach was used. • This approach provided adequate visualization for removal of the tumor., Introduction Large sphenoid ridge meningiomas are surgically challenging because of their extension to adjacent structures. Extracranial meningiomas are very rare; most are of the secondary type and have an intracranial origin. Improved surgical methods are required for treatment of this entity. Presentation of case Here, we describe a case of a huge sphenoid ridge meningioma extending into the sphenoid sinus that was resected by staged transcranial and endoscopic endonasal resection via a transsphenoidal and transpterygoid approach. It was possible to excise the tumor from the sphenoid sinus in a minimally invasive manner via this approach. Discussion and conclusion The transsphenoidal and transpterygoid approach was useful for providing a surgical field that allowed adequate visualization for removal of a sphenoid tumor that had expanded well into the lateral fossa of the sphenoid bone.

Background Applications of machine learning for the early detection of diseases for which a clear-cut diagnostic gold standard exists have been evaluated. However, little is known about the usefulness of machine learning approaches in the decision-making process for decisions such as insulin initiation by diabetes specialists for which no absolute standards exist in clinical settings. Objective The objectives of this study were to examine the ability of machine learning models to predict insulin initiation by specialists and whether the machine learning approach could support decision making by general physicians for insulin initiation in patients with type 2 diabetes. Methods Data from patients prescribed hypoglycemic agents from December 2009 to March 2015 were extracted from diabetes specialists’ registries, resulting in a sample size of 4860 patients who had received initial monotherapy with either insulin (n=293) or noninsulin (n=4567). Neural network output was insulin initiation ranging from 0 to 1 with a cutoff of >0.5 for the dichotomous classification. Accuracy, recall, and area under the receiver operating characteristic curve (AUC) were calculated to compare the ability of machine learning models to make decisions regarding insulin initiation to the decision-making ability of logistic regression and general physicians. By comparing the decision-making ability of machine learning and logistic regression to that of general physicians, 7 cases were chosen based on patient information as the gold standard based on the agreement of 8 of the 9 specialists. Results The AUCs, accuracy, and recall of logistic regression were higher than those of machine learning (AUCs of 0.89-0.90 for logistic regression versus 0.67-0.74 for machine learning). When the examination was limited to cases receiving insulin, discrimination by machine learning was similar to that of logistic regression analysis (recall of 0.05-0.68 for logistic regression versus 0.11-0.52 for machine learning). Accuracies of logistic regression, a machine learning model (downsampling ratio of 1:8), and general physicians were 0.80, 0.70, and 0.66, respectively, for 43 randomly selected cases. For the 7 gold standard cases, the accuracies of logistic regression and the machine learning model were 1.00 and 0.86, respectively, with a downsampling ratio of 1:8, which were higher than the accuracy of general physicians (ie, 0.43). Conclusions Although we found no superior performance of machine learning over logistic regression, machine learning had higher accuracy in prediction of insulin initiation than general physicians, defined by diabetes specialists’ choice of the gold standard. Further study is needed before the use of machine learning–based decision support systems for insulin initiation can be incorporated into clinical practice.

Whether early stages of kidney dysfunction assessed by the estimated glomerular filtration rate from cystatin C measurements (eGFRCysC) rather than from creatinine measurements (eGFRCr) would more precisely reflect the risk of developing type 2 diabetes (T2D) has not been clarified. We compared the risk of developing T2D associated with renal dysfunction indicated by eGFRCysC or eGFRCr measurements.Studied were 2131 Japanese individuals without diabetes. Hazard ratios (HRs) for the development of T2D over 3-5 y were calculated across categories of eGFRCysC and eGFRCr, respectively.Reduced levels of eGFRCysC were associated with a step-wise increase in the cumulative incidence rate of T2D (p=0.007). In comparison with the eGFRCysC85th percentile group (≥ 117.4 ml/min/1.73 m(2)), the lowest group, which was the eGFRCysC15th percentile group (86.2 ml/min/1.73 m(2)), had an adjusted HR of 2.30 (95% CI 1.13, 4.68) for T2D. Compared with the eGFRCr85th percentile group, the lowest eGFRCr group (15th percentile) had an HR of 1.19 (0.63, 2.24) for T2D. However, individuals with eGFRCr60 ml/min/1.73 m(2) had a significantly increased risk of T2D. Clustering of both low eGFRCysC and low eGFRCr further elevated the HR for T2D compared with the presence of either.Although eGFRCr in ranges indicating chronic kidney disease reflected an elevated risk of developing diabetes, earlier stages of kidney dysfunction indicated by reduced eGFRCysC, which could not be captured by reduced eGFRCr, would be a marker for an elevated risk of developing T2D.

Nontypeable Haemophilus influenzae (NTHi) is associated with chronic otitis media (COM). In this study, we generated a murine model of COM by using eustachian tube (ET) obstruction and NTHi (10 7 CFU) inoculation into the tympanic bulla, and we investigated the relationship between regulatory T cells (Treg) and chronic inflammation in the middle ear. Middle ear effusions (MEEs) and middle ear mucosae (MEM) were collected at days 3 and 14 and at 1 and 2 months after inoculation. Untreated mice served as controls. MEEs were used for bacterial counts and to measure the concentrations of cytokines. MEM were collected for histological evaluation and flow cytometric analysis. Inflammation of the MEM was prolonged throughout this study, and the incidence of NTHi culture-positive MEE was 38% at 2 months after inoculation. The levels of interleukin-1β (IL-β), tumor necrosis factor alpha, IL-10, and transforming growth factor β were increased in the middle ear for up to 2 months after inoculation. CD4 + CD25 + FoxP3 + Treg accumulated in the middle ear, and the percentage of Treg in the MEM increased for up to 2 months after inoculation. Treg depletion induced a 99.9% reduction of bacterial counts in MEEs and also significantly reduced the ratio of NTHi culture-positive MEE. The levels of these cytokines were also reduced in MEEs. In summary, we developed a murine model of COM, and our findings indicate that Treg confer infectious tolerance to NTHi in the middle ear.

ObjectiveDeclining healthy life expectancy due to functional disability is relevant and urgent because of its association with decreased quality of life and also for its enormous socioeconomic impact. The aim of this study is to examine the impact of diabetes, hypertension, dyslipidemia and physical activity habits on functional disability among community-dwelling Japanese adults.Research design and methodsThis is a population-based retrospective cohort study including 9673 people aged 39–98 years in Japan (4420, men). Functional disability was defined as a condition meeting Japan’s new long-term care insurance certification requirements for the need of assistance in the activities of daily living whether by caregivers or assistive devices. Cox proportional-hazards regression model identified variables related to functional disability.ResultsMedian follow-up was 3.7 years. During the study period, 165 disabilities occurred in the overall study population. Multivariate analysis showed that diabetes (HR 1.74 (95% CI 1.12 to 2.68)) and no physical activity habit (HR 1.83 (1.27 to 2.65)) presented increased risks for disability. HR for disability increased with the number of risk factors (HR of individuals with four conditions, 3.96 (1.59 to 9.99) vs individuals with none of those conditions as a reference). HR for disability among patients with diabetes with and without a physical activity habit was 1.68 (0.70 to 4.04) and 3.19 (1.79 to 5.70), respectively, compared with individuals without diabetes with a physical activity habit.ConclusionsThe combination of diabetes and lack of habitual physical activity is predictive of functional disability in Japanese. Habitual physical activity attenuates the risk of functional disability in patients with diabetes.

Background Efficacy of programs for patients with diabetes mellitus (DM) that have promoted family members to help with patients’ self-care activities has been largely inconsistent. This meta-analysis aims to assess the effect of family-oriented diabetes programs for glycemic control (GC). Methods Electronic literature searches were conducted for clinical trials with a parallel design wherein there were two groups according to whether family members were included (intervention group) or not included (control group) and changes in glycohemoglobin A1C (A1C) were assessed as a study outcome. Each effect size (i.e. difference in A1C change between the intervention and control group) was pooled with a random-effects model. Results There were 31 eligible trials consisting of 1466 and 1415 patients in the intervention and control groups, respectively. Pooled A1C change [95% confidence interval (CI)] was −0.45% (−0.64% to −0.26%). Limiting analyses to 21 trials targeted at patients with type 1 DM or 9 trials targeted at patients with type 2 DM, the pooled A1C changes (95% CI) were −0.35% (−0.55% to −0.14%) and −0.71% (−1.09% to −0.33%), respectively. Conclusion This meta-analysis suggests that focusing on the family as well as the individual patient in self-management diabetes programs to improve the performance of self-care activities of patients with DM is effective in terms of proper GC.

Although control of multiple risk factors is essential to prevent CAD in persons with and without DM, longitudinal studies are scarce that directly and quantitatively compared effects of such control in DM and non-DM. Thus, we investigated effects on subsequent CAD of the number of controlled risk factors among blood pressure, LDL cholesterol and HbA1c using a nationwide claim-based database (median follow-up 4.8 y) in Japan. Targets were based on ADA and Japanese guidelines. Of 207,029 non-DM persons, 42.8% and 37.9% were at target for 1 and 2 factors, respectively. Of 13,471 persons with DM, 39.5%, 32.1%, and 10.0% were at target for 1, 2, and 3 factors, respectively. Multivariate Cox analysis showed reduced CAD risk with increased numbers of risk factor targets reached in DM compared to non-DM (Table, upper). However, in DM, although fulfillment of the target for only 1 risk factor significantly elevated the hazard ratio (HR) (i.e., 1.98 (1.28-3.07)) to non-significance (i.e., 1.03 (0.68-1.66)), no further significant HR reduction below reference (i.e., non-DM with no target achieved) was found (Table, lower). These findings show that composite control of modifiable risk factors has a larger effect in DM compared to non-DM, but the effect was not sufficient to bring CAD risk in DM below that for non-DM persons with none of 3 risk factors being at target based on current target levels. Disclosure K. Fujihara: None. Y. Matsubayashi: None. M. Kitazawa: None. M. Yamamoto: None. T. Osawa: None. M. Kaneko: None. N. Yamanaka: None. H. Seida: None. K. Kato: None. S. Kodama: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..

Although chronic pancreatitis is a known predictor of type 2 diabetes mellitus (T2DM), no previous studies have determined whether serum amylase (AMY) could be a predictor of T2DM with consideration of fasting plasma glucose (FPG) and HbA1c. We analyzed a historical cohort of 2,238 individuals without T2DM who underwent health examinations on an annual basis with a mean follow-up period of 9.6 y. AMY was categorized into quartiles and a multivariate Cox model was used to estimate the hazard ratio for incident T2DM. During a 10-y follow-up, 228 individuals developed T2DM. Median and interquartile range of baseline AMY(IU/L) was 74(62-91). Baseline AMY was significantly lower for participants who developed T2D compared to those who did not (71(59-84) vs. 75(62-92), p Disclosure D. Ishii: None. K. Fujihara: None. M. Harada: None. M. Ishizawa: None. S. Kodama: None. K. Saito: None. Y. Mori: None. R. Yamamoto-Honda: None. Y. Arase: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..

Although the importance of support of patients by family members is emphasized for diabetes care, evidence of achieving adequate glycemic control (GC) through instructing family members to help in self-management care of diabetes patients has not been established. This meta-analysis assessed the effect of family-oriented diabetes programs on GC. The pooled A1C change shown in 31 studies that were retrieved from systematic literature searches for clinical trials presenting data on the net effect of family education on the reduction in glycohemoglobin A1C (A1C) (i.e., difference in A1C change between intervention groups involving family members and that not involving family members [control group]) was -0.45% (PP Disclosure S. Kodama: None. K. Fujihara: None. H. Ishiguro: Research Support; Self; MSD K.K., Sanofi K.K., Eli Lilly and Company. C. Horikawa: None. Y. Yachi: None. M. Ishizawa: None. S. Matsunaga: None. S. Tanaka: None. K. Kato: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..

Although a so-called “J”- or “U”-shaped relationship between treatment-achieved HbA1c values and risk of coronary artery disease (CAD) has often been reported, it is not yet clarified whether the association is maintained across various treatment modalities including diet only (D) for macro/microvascular complications of diabetes. Thus, we investigated effects of treatment-achieved HbA1c on CAD events and treatment-required diabetic eye disease (TRDED) in 4 treatment subgroups: D, insulin (I), sulfonylurea (S) and antihyperglycemic agents other than glinides, S or I. We utilized a nationwide claims database of 14,633 patients with diabetes in Japan (mean age 50.3 y, HbA1c 7.2%). Cox regression examined CAD and TRDED risk over a 5.1 y follow-up. A significant linear trend in the association between HbA1c and CAD events was only seen in the D group. Significantly higher risks for CAD were observed in the I and S groups whose HbA1c was ≤7.0% or S compared to D group patients with HbA1c ≤7.0%. Conversely, risk for TRDED was strongly dependent on achieved HbA1c regardless of treatment modalities. However, risks of TRDED did not differ significantly between categories of ≤7.0% and 7.1-8.0% among S and I groups. These results implied the necessity of setting different target HbA1c goals according to treatment modalities for prevention of micro-/macrovascular complications. Disclosure M. Harada: None. K. Fujihara: None. T. Osawa: None. M. Yamamoto: None. M. Kaneko: None. Y. Matsubayashi: None. S. Matsunaga: None. T. Yamada: None. N. Yamanaka: None. H. Seida: None. S. Kodama: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..