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Semen analysis has long been used to evaluate male fertility. Recently, several sperm function tests have been developed. Of those, the sperm DNA fragmentation index (DFI), which describes the status of the sperm DNA, is thought to be a suitable parameter for evaluating male fertility. However, there have been no large-scale studies on the sperm DFI of Japanese men. Therefore, we investigated the feasibility of using an in-house flow cytometry-based sperm DFI analysis based on the sperm DNA fragmentation test of sperm chromatin structure assay (SCSA) to assess male fertility in Japan. This study enrolled 743 infertile and 20 fertile Japanese men. To evaluate reproducibility, inter- and intraobserver precision was analyzed. A receiver operating characteristic curve analysis was used to set a cutoff value for the sperm DFI to identify men who could father children by timed intercourse or intrauterine insemination. The variability of the sperm DFI among fertile volunteers was determined. The relationship between semen parameters and the sperm DFI was assessed by Spearman's rho test. A precision analysis revealed good reproducibility of the sperm DFI. The cutoff value of sperm DNA fragmentation in infertile men was 24.0%. Semen volume had no relationship with the sperm DFI. Sperm concentration, sperm motility, total motile sperm count, and percentage of normal-shaped sperm were significantly and negatively correlated with the sperm DFI. The median sperm DFI was smaller in fertile volunteers (7.7%) than that in infertile men (19.4%). Sperm DNA fragmentation analysis can be used to assess sperm functions that cannot be evaluated by ordinary semen analysis.

AIMS/INTRODUCTION Metformin is associated with the risk of gastrointestinal complications, and probiotic Bifidobacterium bifidum G9-1 (BBG9-1) can improve the symptoms of diarrhea. This study aimed to clarify the effects of probiotic BBG9-1 on the gastrointestinal symptoms of type 2 diabetes mellitus patients using metformin. MATERIALS AND METHODS In this open-label single-arm exploratory study, 40 patients (mean age 64.0 ± 9.4 years) were given probiotic BBG9-1 for 10 weeks. Changes in the gastrointestinal symptom rating scale total score, which was the primary end-point, gastrointestinal symptom rating scale subscale scores, glycated hemoglobin levels and gut microbiota after the administration of probiotic BBG9-1 were evaluated by the Student's t-test. RESULTS The gastrointestinal symptom rating scale total score significantly improved (from 2.02 ± 0.51 to 1.59 ± 0.43, change, -0.43 ± 0.49, P

Aims/Introduction Body fluid volume imbalance is common in patients with kidney failure, and is associated with all‐cause mortality. This study aimed to investigate the association between fluid volume imbalance and albuminuria in patients with type 2 diabetes mellitus without kidney failure. Materials and Methods Using data from one cohort study, a baseline cross‐sectional study of 432 participants and a longitudinal cohort study of 368 participants who could follow up was carried out. Body fluid imbalance was determined by measuring the extracellular water (ECW)‐to‐intracellular water (ICW) ratio (ECW/ICW) using bioelectrical impedance analysis. A change in the urinary albumin‐to‐creatinine ratio (ACR) was defined as the ratio of urinary ACR at follow up to that at baseline. The ECW/ICW ratio was compared with the level of albuminuria. Results In this cross‐sectional study, the ECW/ICW ratio increased with the level of albuminuria. There was an association between the ECW/ICW ratio and logarithms of urinary ACR after adjusting for covariates (β = 0.205, P 300 mg/gCr, was 0.648 (area under the curve 0.78, 95% confidence interval 0.58–0.90). Conclusions The ECW/ICW ratio is independently associated with the level of albuminuria in patients with type 2 diabetes mellitus without kidney failure. This reinforces the importance of monitoring fluid balance in patients with type 2 diabetes mellitus., Fluid imbalance occurred in diabetes patients without kidney failure, and was associated with the level of albuminuria. The extracellular water to intracellular water ratio is independently associated with changes in albuminuria in patients with type 2 diabetes mellitus without kidney failure. Clinicians need to pay more attention to monitoring the fluid status among patients with type 2 diabetes mellitus, and maintaining fluid balance in the early stage of diabetic kidney disease.

Aims/Introduction Sarcopenia and visceral obesity are major global public health issues, and higher mean corpuscular volume (MCV) levels are related to adverse outcomes. Nevertheless, no study has determined the association between MCV and body composition. Therefore, we evaluated the association between MCV levels and trunk muscle quality, muscle quantity and visceral fat area. Materials and Methods In our cross‐sectional study, we investigated 702 middle‐aged Japanese individuals without anemia and with normal MCV levels who underwent physical checkups. The cross‐sectional area of skeletal muscle or visceral fat was analyzed by computed tomography. Results In the adjusted model, the MCV was independently associated with the visceral fat area index (β = −0.107, P = 0.0007), total skeletal muscle index (β = 0.053, P = 0.0341) and total skeletal muscle density (β = 0.099, P = 0.0012). MCV as a continuous variable was related to the prevalence of sarcopenia (odds ratios [OR] 0.93, 95% confidence intervals (CI) 0.88–0.98, per 1.0 fL increment; P = 0.0097) and visceral obesity (OR 0.91, 95% CI 0.86–0.97, per 1.0 fL increment; P = 0.0046). The highest MCV quartile was independently associated with the prevalence of sarcopenia (OR 0.48, 95% CI 0.27–0.83; P = 0.0089) and visceral obesity (OR 0.49, 95% CI 0.27–0.88; P = 0.0170), compared with the lowest quartile. Conclusions In individuals without anemia and with normal MCV levels, a lower MCV was associated with unfavorable body composition, including lower muscle quality, lower muscle quantity, sarcopenia and visceral obesity., Lower mean corpuscular volume was associated with unfavorable body composition. Mean corpuscular volume was associated with the prevalence of sarcopenia or visceral obesity.

Summary Background & aims Metabolic syndrome (MS) is associated with adverse outcomes, and visceral adipose tissue (VAT) is associated with MS. Recently, VAT has been classified into intraperitoneal VAT (IVAT) and retroperitoneal VAT (RVAT). This study aimed to evaluate the association of IVAT and RVAT with the prevalence of MS or its components. Methods In our cross-sectional study, the prevalence of MS or its components was analyzed in 803 middle-aged Japanese participants. The cross-sectional area of the abdominal adipose tissue was evaluated from an unenhanced computed tomography scan at the third lumbar vertebra, and IVAT or RVAT was analyzed using a specialized software. The areas were normalized for the square of the participants’ height in meters and described as the IVAT or RVAT area index. Results In age, sex, and BMI adjusted model, the IVAT, or RVAT area index was independently associated with the prevalence of MS. After simultaneous inclusion of IVAT, RVAT, and deep and superficial subcutaneous adipose tissue area indices for multivariate logistic regression analysis, the IVAT area index was found to be independently associated with the prevalence of MS (adjusted odds ratio [OR], 1.03; 95% confidence intervals [CI], 1.02–1.08) and its components, including waist circumference (OR, 1.07; 95% CI, 1.03–1.10), glucose (1.03; 1.01–1.05), triglycerides (1.03; 1.00–1.05), and high-density lipoprotein cholesterol (1.03; 1.00–1.05), whereas the RVAT area index was not. The RVAT area index was independently associated with the prevalence of component-blood pressure (1.06; 1.02–1.11), whereas the IVAT area index was not. Conclusions IVAT and RVAT are associated differently with the prevalence of MS and its components.

Objectives To evaluate whether the long-term usage of mirabegron, which was reported to have potential side effects on male reproductive organs in animal studies, was harmful to spermatogenesis in human testis. Methods Thirty consecutive patients with spinal cord injury (20-48 years old) who performed clean intermittent catheterization were involved in this study. Ten patients were treated with mirabegron (50 mg/d) for more than 2 years and refrained from using an antimuscarinic agent due to the side effects of constipation and dry mouth. Twenty patients were treated with neither anticholinergic agents nor mirabegron. All underwent conventional testicular sperm extraction. The sperm recovery rate and histopathologic findings of the retrieved testicular tissue were compared between both groups. Results We found no difference in the sperm recovery rate (P = .083) between both groups. Spinal cord injury patients treated with mirabegron had better spermatogenesis than those not treated with mirabegron (P Conclusions From these data, we conclude that the therapeutic dose of mirabegron had no harmful effect on spermatogenesis in spinal cord injury patients of reproductive age.

Background/aim Curcumin is a natural compound of turmeric, which inhibits prostate cancer cell proliferation. This study examined whether treatment of LNCaP prostate cancer cells with the combination of curcumin and dutasteride, a 5-alpha reductase inhibitor, affect proliferation and the amount of testosterone and dihydrotestosterone. Materials and methods LNCaP Cells were incubated with curcumin or the combination of curcumin and dutasteride and cell proliferation was measured at 72 h. LC-MS/MS was used to determine testosterone and dihydrotestosterone concentrations in prostate cancer cells. Results Curcumin combined with dutasteride suppressed proliferation and affected apoptosis of LNCaP cells. The combination of curcumin and dutasteride also reduced the amount of testosterone and dihydrotestosterone in LNCaP cells. The secretion of prostate-specific antigen was inhibited by the combination treatment in a dose-dependent manner. Conclusion Treatment with the combination of curcumin and dutasteride may interfere with the intra-tumoral androgen activity.

Background The coexistence of hypertension and diabetes mellitus significantly increases the risk of macrovascular complications in patients with diabetes. Home blood pressure is important because it is more strongly associated with target organ damage and total mortality than clinic blood pressure measurements. Regular moderate aerobic exercise has antihypertensive effects. This study aims to examine the effect of aerobic exercise therapy on blood pressure at home in patients with diabetes. Patients and methods In this crossover randomized controlled trial, 110 patients with type 2 diabetes will be randomly assigned to two groups: an exercise preceding group and an exercise lagging group. During the exercise period, patients will be instructed to walk either 30 minutes twice each day or 60 minutes once each day for at least 3 days per week. During the non-exercise period, patients will be permitted to perform physical activity associated with activities of daily life. Patients will be followed up for 56 days. The primary outcome will be the mean nocturnal blood pressure from day 24 to 28 during the exercise period compared to that during the non-exercise period. The secondary outcome will include variation in nocturnal blood pressure, mean blood pressure values and variation of morning and evening blood pressure from day 24 to 28 in the exercise period compared to the non-exercise period, body weight, body mass index and bioelectrical impedance analysis. Biochemical tests such as hemoglobin A1c level, blood glucose level, serum lipid profile, renal function, uric acid levels and liver function tests will also be measured. Discussion This randomized controlled trial will provide critical information regarding the effectiveness of moderate exercise on nocturnal blood pressure reduction. If successful, the results of this randomized controlled trial may increase exercise motivation in people with diabetes and may lead to improvement or prevention of target organ damage and overall mortality. Trial registration Trial registration: University Hospital Medical Information Network, UMIN 000035973. Protocol version number: R000040969. Registration date: February 22, 2019. Recruitment began: June 19, 2019. The date of completion of recruitment: July 3, 2020. URL: http://www.umin.ac.jp.

Higher hemoglobin levels are associated with incident metabolic syndrome (MetS), and higher mean corpuscular volume (MCV) is associated with adverse outcomes. The objective of this study is to evaluate the combined effect of MCV and hemoglobin levels on incident MetS.In our cross-sectional study, we analyzed the prevalence of MetS in 20,162 middle-aged Japanese subjects without anemia and with normal MCV levels, as they underwent physical checkups. We subsequently analyzed incident MetS in 11,110 subjects. In order to evaluate the combined effect on incident MetS, the subjects were divided into four study groups according to cutoff values of hemoglobin and MCV for identifying the prevalence of MetS.In the cross-sectional study, hemoglobin (adjusted odds ratio [aOR], 1.02; P 0.0001 in men and OR, 1.04; P 0.0001 in women, per 1.0 g/L) and MCV (aOR, 0.93; P 0.0001 in men and OR, 0.94; P = 0.0005 in women, per 1.0 fL) were independently associated with the prevalence of MetS. In the longitudinal cohort study, hemoglobin (adjusted hazards ratio [aHR, 1.12; P = 0.0006, per 1.0 g/L) and MCV (aHR, 0.96; P 0.0001, per 1.0 fL) were independently associated with incident MetS in men but not in women. Then, the lower hemoglobin/higher MCV group showed decreased HRs for incidence of MetS compared with other groups of men but not of women.Among the subjects without anemia and with normal MCV levels, higher hemoglobin or lower MCV levels were associated with higher prevalence of MetS in men and women. In addition, lower hemoglobin with higher MCV showed a decreased risk of MetS in men. We suggested that the assessment of hemoglobin and MCV levels could be used as practical screening tool for MetS.

Purpose Cryptorchidism is one of the most common causes of non‐obstructive azoospermia (NOA) in adulthood. Even if early orchidopexy is performed to preserve fertility potential, some patients still suffer from azoospermia. Fertility potential is significantly lower in bilateral than unilateral cryptorchidism. The aims of this study were to identify clinical parameters that predict the likely success of sperm recovery by microscopic testicular sperm extraction (micro‐TESE) and also the likely outcome of intracytoplasmic sperm injection using sperm from NOA patients who submitted to bilateral orchidopexy. Methods Fifty‐two NOA patients with a history of bilateral cryptorchidism underwent micro‐TESE. The following clinical parameters were evaluated as predictive factors for successful sperm recovery: age at micro‐TESE; age at orchidopexy; period from orchidopexy to micro‐TESE; luteinizing hormone (LH); follicle‐stimulating hormone (FSH); testosterone; average testicular volume; and body mass index. Results In the successful sperm retrieval group, average testicular volume was significantly greater, while serum LH and FSH, and body mass index were significantly lower. In a multivariate analysis, average testicular volume was positively correlated with successful sperm recovery. Conclusion Our results indicate that testicular volume in NOA patients with bilateral cryptorchidism is a predictor for successful sperm recovery.

Background and aims The metabolic syndrome has been reported by cross-sectional studies to have an association with skeletal muscle quality and quantity. Using a longitudinal study design, this study aimed to explicate the association between muscle characteristics assessed with computed tomography (CT) and the incidence and progression of metabolic syndrome. Methods and results In this retrospective study on a cohort of employees undergoing annual physical examinations, we evaluated data from 554 participants without metabolic syndrome. The cross-sectional skeletal muscle area was determined based on CT data at the level of the third lumbar vertebra, and the skeletal muscle density (SMD) and skeletal muscle index (SMI) were measured. The participants were divided into four study groups according to the sex-specific median values for SMI and SMD. We followed the participants for a mean period of 3.1 years. In the sex- and age-adjusted model, SMI and SMD had an interaction effect on the longitudinal change in number of metabolic syndrome components (β = −0.074, p = 0.0727). Multiple regression analyses revealed that both low SMI and SMD was significantly associated with the change (β = 0.131, p = 0.0281), whereas the low SMI and high SMD, and high SMI and low SMD were not. Both low SMI and SMD (hazard ratio (HR), 2.42; 95% confidence interval, 1.28–4.78) showed an increased adjusted HR for incident metabolic syndrome. Conclusion The participants with both low quality and quantity of skeletal muscles were associated with the incidence and progression of metabolic syndrome, whereas those with only low quantity or quality of skeletal muscles were not.

The present study investigated the antitumor activity and chemopreventive effects of a nanoparticle formulation of curcumin in preclinical models of mouse Pten-deficient prostate cancer. The antitumor activity of the nanoparticle curcumin was evaluated in mouse castration-naïve (7113-D3) and castration-resistant prostate cancer (2945-E10) derived cell lines in vitro. Cell viability was reduced in both cell lines in a dose and time-dependent manner. The effects of long-term dietary supplementation with the nanoparticle curcumin formulation were evaluated in a conditional Pten-deficient mouse model. Prostate tissues from Pten-deficient prostate cancers were obtained after sixteen weeks of dietary supplementation of 76 mg/kg/day or 380 mg/kg/day nanoparticle curcumin. Daily supplementation of nanoparticle curcumin did not affect mouse bodyweights or spleen size but did result in enlargement of the liver. Dietary supplementation did not influence tumor burden, however, mice fed high-dose curcumin had lower cancer cell proliferation rates at 12 and 16 weeks of age. Together, these results show that daily supplementation of a nanoparticle formulation of curcumin is tolerable and suggest that curcumin could have chemopreventive activity in early-stage prostate cancer.

Purpose Mosaic loss of chromosome Y (mLOY) is a common feature in elderly men. If mLOY can also occur in young men, it may lead to spermatogenic failure due to loss of spermatogenic genes. Indeed, previous studies detected the 45,X/46,XY karyotype in a few young men with spermatogenic failure. The present study aimed to clarify the frequency of cryptic mLOY in reproductive‐aged men with spermatogenic failure. Methods We studied 198 men at ages 24‐55 years who presented with etiology‐unknown non‐obstructive azoospermia. Prior this study, these patients underwent G‐banding analysis for 20 leukocytes and were found to have 46,XY karyotype. We analyzed copy numbers of chromosome Y in blood cells by using semi‐quantitative multiplex PCR for AMELY/AMELX, array‐based comparative genomic hybridization (CGH) for the AMELY locus, and droplet digital PCR for SRY, USP9Y, and UTY. Results Multiplex PCR showed borderline low AMELY/AMELX ratios in three patients. However, for the three patients, CGH excluded deletion of the AMELY locus, and droplet digital PCR suggested preserved copy numbers of all tested loci. Conclusion This study highlights the rarity of leukocyte mLOY in reproductive‐aged men with spermatogenic failure. In addition, our data imply that standard karyotyping is sufficient to screen early onset mLOY.

BackgroundSarcopenia has reportedly been associated with increased risk of mortality in general populations. However, few studies have investigated the association between sarcopenia and mortality in older people with type 2 diabetes mellitus (T2D). This study aimed to investigate the effect of sarcopenia on incident all-cause mortality in older people with T2D.MethodsLow muscle strength were set at handgrip strength 2 for men and 2 for women. People who had both low muscle strength and low SMI were diagnosed with sarcopenia. Due to a low incidence of all-cause mortality, the propensity score was used. The propensity score was evaluated using multivariable logistic regression models with the following parameters: age, sex, duration of diabetes, history of heart disease, history of cancer, smoking, exercise, alcohol, sodium-glucose cotransporter-2 inhibitor, glucagon-like peptide-1 receptor agonist, insulin, corticosteroid, hypertension, body mass index, glycosylated hemoglobin A1c, triglycerides, and creatinine, and the C-statistic was 0.89.ResultsIn this prospective cohort study, 396 people with an average age and duration of diabetes of 71.3 (6.3) years and 16.3 (11.3) years, respectively, were included. Of those included, 14.6% had sarcopenia. During the average 40.5 (16.5) months of follow-up, 13 people (6 out of the 338 without sarcopenia and 7 out of the 58 with sarcopenia) died. Incident rate were 5.1/1000 person years of follow-up in people without sarcopenia and 41.3/1000 person years of follow-up in people with sarcopenia. According to Cox regression analysis, sarcopenia was associated with all-cause mortality (adjusted hazard ratio: 6.12, 95% confidence interval: 1.52–24.7, p = 0.011).ConclusionSarcopenia is associated with incident all-cause mortality in older outpatients with T2D.

AIM/INTRODUCTION As the association between a fasting glucose concentration of 90-99 mg/dL and the onset of type 2 diabetes is still controversial, we aimed to assess it in 37,148 Japanese individuals with a normal plasma glucose concentration. MATERIALS AND METHODS This long-term retrospective cohort study included individuals having a medical checkup at Panasonic Corporation from 2008 to 2018. In total, 1,028 participants developed type 2 diabetes. RESULTS Cox regression analyses revealed that the risk for the onset of diabetes increased by 9.0% per 1 mg/dL increase in fasting plasma glucose concentration in subjects with the concentration ranging from 90 to 99 mg/dL. Compared with individuals with a fasting glucose concentration of ≤89 mg/dL, the adjusted hazard ratios for developing diabetes were 1.53 (95% CI; 1.22-1.91), 1.76 (95% CI; 1.41-2.18), 1.89 (95% CI; 1.52-2.35), 3.17 (95% CI; 2.61-3.84), and 3.41 (95% CI; 2.79-4.15) at fasting plasma glucose concentrations of 90-91, 92-93, 94-95, 96-97, and 98-99 mg/dL, respectively. In populations with obesity, the adjusted hazards ratios for developing diabetes were 1.56 (95% CI; 1.15-2.09), 1.82 (95% CI; 1.37-2.40), 2.05 (95% CI; 1.55-2.69), 3.53 (95% CI; 2.79-4.46), and 3.28 (95% CI; 2.53-4.22) at fasting plasma glucose concentrations of 90-91, 92-93, 94-95, 96-97, and 98-99 mg/dL, respectively. CONCLUSIONS This study demonstrates that the risk of type 2 diabetes among subjects having a fasting plasma glucose concentration of 90-99 mg/dL, is progressively higher with an increasing level of fasting plasma glucose concentration in a Japanese people.

Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease commonly observed around the Mediterranean basin presenting as recurrent febrile episodes. We herein describe a Japanese case of genetically-confirmed FMF, in which fever was lacking during attacks. An otherwise healthy 34-year-old man presented with frequent episodes of abdominal pain, which resolved spontaneously. During the attacks, the patient was afebrile, but the inflammatory marker levels in his blood were increased. Abdominal CT demonstrated enhancement of the jejunal membrane. After the initiation of colchicine therapy, the patient experienced no attacks for more than one year. The diagnosis of FMF was confirmed by a genetic analysis.

Varicocele is a common cause of male infertility. It is reported that low sperm concentration, motility and morphology are indicative of increased sperm DNA fragmentation index (DFI) in men with varicocele. Although research has been conducted into the relationship between varicocele and DFI, little is known about seminal oxidation-reduction potential (ORP) in varicocele patients. We assessed the relationship between varicocele with seminal ORP and sperm DFI in both fertile and infertile men. This prospective case-control study compared the findings from infertile men with varicocele to those of men with normal spermatogenesis without varicocele. Semen samples were collected and assessed using the WHO (2010) guidelines. ORP was measured (mV) and normalized to sperm concentration (mV/10

Background: Glycemic variability is a risk factor for total death and cardiovascular events. There are no obvious guidelines for the direct treatment of glycemic variability, but it can be improved with the treatment of postprandial hyperglycemia. Objective: We compared the effect of repaglinide versus the combination of mitiglinide and voglibose, used to improve postprandial hyperglycemia, on glycemic variability in Japanese patients with type 2 diabetes. Methods: We performed an open-label randomized cross-over trial between April 2016 and April 2018. Patients with type 2 diabetes who were admitted to our hospital were enrolled in our study (n = 12). Glycemic variability was assessed using a continuous glucose monitoring system. Results: The average glucose level of the repaglinide phase (146.1 ± 20.7 mg/dl) and the combination of mitiglinide and voglibose phase (132.3 ± 19.8 mg/dl) were similar (P = 0.10). The standard division (P = 0.0005), coefficient of variation (P = 0.006), and mean amplitude of glycemic excursion (P = 0.002) of glucose were lower in the combination of mitiglinide and voglibose phase than in the repaglinide phase. Conclusion: Treatment with the combination of mitiglinide and voglibose might be more effective than repaglinide for the improvement of glycemic variability.

Aims/Introduction Diabetic kidney disease has been considered as an important risk factor of cardiovascular disease. Chronic hypoxia is considered to be the main cause of renal injury. Diminished microcirculatory blood flow could be associated with hypoxia in the kidney. Whether diminished microcirculation is associated with diabetic kidney disease has not yet been reported. Here, we investigated the correlation between microcirculatory function and diabetic kidney disease in patients with type 2 diabetes. Materials and Methods Our cross‐sectional study included 574 patients who were admitted to Matsushita Memorial Hospital in Moriguchi, Japan, for type 2 diabetes. Microcirculatory function was assessed using the perfusion index (PI), which represents the level of circulation through peripheral tissues. We measured the PI for all patients. Results The median age and PI values were 70 years (range 60–77 years) and 2.8% (range 1.6–4.8%). Multiple regression analyses showed that the PI independently correlated with the logarithm of urinary albumin excretion (P = 0.009) and estimated glomerular filtration rate (P = 0.005), respectively. Multiple logistic regression analyses showed that patients with systolic blood pressure (SBP) greater than the median and PI less than or equal to the median (high‐low group) had a significantly increased odds of albuminuria compared with those with SBP less than or equal to the median and PI greater than the median (low‐high group), and patients with SBP greater than the median and PI less than or equal to the median (high‐low group) had a significantly increased odds of estimated glomerular filtration rate, Perfusion index could be a novel indicator of diabetic kidney disease in patients with type 2 diabetes.

Metformin is associated with risks of gastrointestinal complications in patients with type 2 diabetes. In contrast, probiotic Bifidobacterium bifidum G9-1 (BBG9-1) could improve the symptoms of diarrhea caused by metformin in animal models. Thus, the primary outcome of this study will be the effect of the probiotic BBG9-1 on gastrointestinal symptoms, including diarrhea, in patients with type 2 diabetes who use metformin. This open-label, single-arm, and exploratory study will examine 40 patients with type 2 diabetes who use metformin and have symptoms of constipation or diarrhea. After the baseline examination (objective 1), patients will be administered probiotic BBG9-1 for 10 ± 2 weeks. Then, examinations will be performed (objective 2). The primary outcome will be changes in the symptoms of constipation or diarrhea from objective 1 to objective 2. Secondary outcomes will include changes in gut microbiota, and correlations between changes in fecal properties and biomarkers, including HbA1c level and body mass index. This is the first study to investigate the effect of probiotic BBG9-1 on the change in the symptom of constipation or diarrhea in patients with type 2 diabetes who use metformin.

Masakazu Ichinose,1 Yasushi Fukushima,2 Yoshikazu Inoue,3 Osamu Hataji,4 Gary T Ferguson,5 Klaus F Rabe,6 Nobuya Hayashi,7 Hiroshi Okada,7 Mami Takikawa,7 Eric Bourne,8 Shaila Ballal,9 Kiernan DeAngelis,10 Magnus Aurivillius,11 Colin Reisner,9 Paul Dorinsky8 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Fukuwa Clinic, Tokyo, Japan; 3Clinical Research Center, National Hospital Organization, Kinki-Chuo Chest Medical Center, Osaka, Japan; 4Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Japan; 5Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 6LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Großhansdorf, Germany; 7AstraZeneca K.K., Osaka, Japan; 8AstraZeneca, Durham, NC, USA; 9AstraZeneca, Morristown, NJ, USA; 10Formerly of AstraZeneca, Durham, NC, USA; 11AstraZeneca, Gothenburg, SwedenCorrespondence: Masakazu IchinoseDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8534Email ichinose@rm.med.tohoku.ac.jpBackground: Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) is a triple fixed-dose combination for COPD. The long-term safety of triple therapy for COPD has not been investigated in Japanese patients. In this 28-week extension study (NCT03262012), we investigated the long-term safety and tolerability of BGF MDI in Japanese patients with moderate-to-very severe COPD who completed the 24-week Phase III randomized, double-blind, multicenter KRONOS study (NCT02497001).Materials and methods: Patients randomized to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily in KRONOS continued treatment for up to 28 additional weeks. Safety was evaluated over 52 weeks via adverse event (AE) monitoring, electrocardiograms, clinical laboratory testing, and vital sign measurements.Results: The safety population included 416 patients who received BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Treatment-emergent AE (TEAE) rates were similar across treatment groups (range: 82.6–82.9%). The most frequent TEAEs overall were nasopharyngitis (32.2%) and bronchitis (9.9%). The incidence of major adverse cardiovascular events was low across groups (range: 0.0–2.9%). Over 52 weeks, the incidence of confirmed pneumonia was 9.4% (BGF MDI), 3.6% (GFF MDI), 5.7% (BFF MDI), and 2.9% (BUD/FORM DPI); in the 28-week extension period, rates were comparable across groups (range: 2.9–5.7%). Six deaths were reported (0.7–2.2% per group); none were considered treatment-related. No clinically meaningful trends were observed in electrocardiograms, laboratory parameters, or vital signs over time in any of the treatment groups.Conclusion: All treatments were well tolerated over 52 weeks, and the safety profile of BGF MDI was generally comparable to dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) and inhaled corticosteroid (ICS)/LABA therapies. These findings support the long-term tolerability of BGF MDI in Japanese patients with COPD.Keywords: co-suspension delivery technology, ICS/LAMA/LABA, inhaled corticosteroid, long-acting muscarinic antagonist, long-acting β2-agonist, Japan

Background & aims Sarcopenia is reported to be associated with nonalcoholic fatty liver disease (NAFLD). Evaluation of skeletal muscle attenuation and area by computed tomography (CT) may represent a promising approach for evaluation of the risk of NAFLD. We examined the association between skeletal muscle characteristics and NAFLD and investigated the combined effect of these parameters on the prevalence of NAFLD. Methods In this cross-sectional study, we analysed data from 632 middle-aged Japanese subjects without daily alcohol intake (353 men and 279 women) from a cohort of employees undergoing annual health examinations. The cross-sectional skeletal muscle area was evaluated on the basis of CT data at the level of the third lumbar vertebrae, and the skeletal muscle index (SMI) and density (SMD) were calculated. The subjects were divided into four study groups according to their SMI and SMD relative to median values. Results One hundred forty men and forty-three women had NAFLD. Total SMI (odds ratio [OR] per 1.0 cm2 /kg/m2 increase 0.43, 95% confidence interval [CI] 0.29-0.64 in men and OR 0.21, 95% CI 0.10-0.42 in women) and total SMD (OR, per 1.0 Hounsfield Unit increase 0.88, 95% CI 0.83-0.93 in men and 0.88, 0.82-0.95 in women) were significantly associated with the prevalence of NAFLD after adjusting for covariates. The subgroup with simultaneous presence of low SMI and low SMD was associated with a significantly higher prevalence of NAFLD compared with other groups. Conclusions Both SMI and SMD are independently associated with the prevalence of NAFLD.

Salt intake is often estimated by the amount of sodium excreted in urine, and miso has been reported to increase it. This cross-sectional study investigated the relationship between obesity and high estimated salt intake with and without habitual miso consumption. Estimates of salt intake (g/day) were calculated using urinary sodium excretion, and a high estimated intake was defined as greater than the median amount of 9.5 g/day. Participants were divided into four groups based on estimated salt intake and miso consumption. Among 300 people, the proportions of obesity were 77.8% (n = 14/18), 40.2% (n = 53/132), 26.0% (n = 33/127), and 34.8% (n = 8/23) in the (+/-), (+/+), (-/+), and (-/-) groups of high estimated salt intake/habitual miso consumption, respectively. Compared with the (+/-) group, the adjusted odds ratios for obesity were 0.07 (95% confidence interval (CI): 0.02–0.26, p &lt, 0.001), 0.16 (95% CI: 0.03–0.76, p = 0.022), and 0.14 (95% CI: 0.04–0.51, p = 0.003) in the (-/+), (-/-), and (+/+) groups, respectively. The presence of obesity was not much higher in people with high estimated salt intake with habitual miso consumption than that in people without. Clinicians should be aware that miso consumption promotes salt excretion, which may lead to an apparently higher estimated salt intake than actual.

Objectives: We verified the clinical usefulness of an approach method in which a physician gives simple salt reduction instructions during outpatient visits to patients with type 2 diabetes. Methods: This study was an open-blind, randomized controlled trial. Subjects were outpatients with type 2 diabetes whose estimated salt intake using spot morning urine sample exceeded the target of salt intake. The control group (CG) was notified only of the current salt intake, whereas the intervention group (IG) was given the brief salt reduction instruction by a physician in addition to the information regarding their current salt intake. Results: The change in estimated salt intake was −0.6 g (from 10.1 to 9.5 g, p = 0.029) in the CG after 8 weeks, and −0.9 g (from 10.1 to 9.2 g, p = 0.001) in the IG, although there were no significant differences between them (p = 0.47). After 24 weeks, both groups no longer differed significantly from the baseline. In addition, multivariate linear regression analyses indicated that high salt intake and low estimated glomerular filtration rate at baseline were significantly associated with salt reduction after 8 weeks. Conclusions: Salt-reducing effects were observed after 8 weeks in both the IG and CG, but no significant difference was observed. Moreover, patients with high salt intake and renal disfunction may be more effective in accepting salt reduction instructions. Making patients aware of the importance of salt reduction through a physician is effective for continuous salt reduction, and it is important to continue regular and repetitive guidance.

Objective: Contrasting results have been reported for the association between the variability in body weight and development of diabetes. No study has elucidated the association between the variability in body weight and the development of type 2 diabetes in a population without obesity and without body weight gain or loss during the study period. In the present study, we evaluated the association between the variability in body mass index (BMI) and development of type 2 diabetes in 19,412 Japanese participants without obesity and without body weight gain or loss during the study period. Methods: We recorded body weight of the participants consecutively each year in Panasonic Corporation, Osaka, Japan from 2008 to 2014 to evaluate the variability of BMI. The participants with obesity (BMI ≥ 25 kg/m2) at baseline and body weight gain or loss from 2008 to 2014 (delta BMI ≥ ± 1 kg/m2) were excluded from the study. We used coefficient of variation (CV) to represent the variability in BMI during 6 years of the study period. Results: In total, 416 participants among all participants (315 participants among those without IFG at baseline) developed type 2 diabetes from 2015 to 2018. The risk of developing type 2 diabetes was higher in the fourth quartile of CV of BMI than that in the lowest quartile (first quartile; reference) of CV of BMI in all participants and in those without IFG at baseline (hazard ratio, 1.33; 95% CI, 1.01-1.75 and hazard ratio, 1.51; 95% CI, 1.10-2.08, respectively). The risk for developing diabetes increased by 11.1% and 15.0% per 1% increase in CV of BMI in all participants and in those without IFG at baseline, respectively. Age, BMI at baseline, HDL cholesterol, glucose, current smoking habit, and fast eaters were also associated with the increased odds of developing type 2 diabetes. Conclusions: In conclusion, the variability in BMI is a risk factor for the development of diabetes in the Japanese population. Disclosure H. Okada: None. M. Hamaguchi: Research Support; Spouse/Partner; AstraZeneca K. K. M. Fukui: None.

Background and Objective: The safe method of instructing insulin dose reduction in combination with SGLT2 inhibitors, dapagliflozin for patients with type 1 diabetes mellitus has not been clarified. In this study, we conducted a stratified, two-arm, parallel comparative study with the primary endpoint of decreasing the frequency of hypoglycemia by instructing basal insulin dose reduction. Method: The basal insulin dose to total daily insulin dose (TDD) ratio was defined as less than 40% in group A and more than 40% in group B. Group B was instructed to reduce basal insulin dose, while group A was not. Results: Twenty-nine patients in group A and 28 patients in group B were included in the analysis due to withdrawal of consent before the start of the study. The frequency of hypoglycemia before and after the intervention was 0.23 times/day in group A to 0.26 times/day and 0.19 times/day in group B to 0.23 times/day, with no significant difference between the two groups (P=0.69). The frequency of ketosis, a secondary endpoint, also increased significantly after the intervention, from 0.013 times/day to 0.086 times/day in Group A (p=0.013) and from 0.013 times/day to 0.059 times/day in Group B (p=0.011). Time In Range on FGM improved from 63.6% to 69.7% in group A and from 59.0% to 69.1% in group B. MAGE improved from 121.7 mg/dL to 105.0 mg/dL in group A and from 123.4 mg/dL to 108.0 mg/dL in group B. DTSQ showed a significant improvement in question 2 regarding hyperglycemia in both groups after the intervention, from 3.6 to 2.5 (p=0.008) in group A and from 3.7 to 2.8 (p=0.017) in group B. Conclusion: In the patients who were able to self-adjust their insulin dose, there was no significant difference in the number of hypoglycemia occurrences after concomitant use of dapagliflozin with or without instruction to reduce basal insulin dose. Concomitant use of dapagliflozin resulted in less glycemic variability, prolonged TIR and improved patient satisfaction regarding with hyperglycemia. Disclosure M. Hamaguchi: Research Support; Spouse/Partner; AstraZeneca K. K. M. Yamazaki: None. T. Tanaka: None. M. Ishii: None. H. Okada: None. K. Mitsuhashi: None. N. Kitagawa: None. G. Hasegawa: None. M. Fukui: None. Funding AstraZeneca K.K.; Ono Pharmaceutical Co., Ltd.

We investigated the feasibility of agarose-gel microcapsules to cryopreserve extremely small numbers of sperm for assisted reproductive technology. Semen samples were collected from 16 patients attending the center for reproductive medicine male infertility clinic at a university hospital. We used agarose microcapsules to cryopreserve extremely small numbers of sperm from 16 patients with male infertility (10 with sperm concentration ≥1 million/mL; 6 with sperm concentration1 million/mL). Six spermatozoa were injected into agarose-gel microcapsules and cryopreserved in a liquid nitrogen tank for 7 days. The Crytop method was used for cryopreservation as a control. After thawing, spermatozoa were recovered. Sperm recovery rates, motility and viability, and recovery time were compared.The post-thawing recovery rate, motility rate, and viability rate were higher whereas the recovery time was shorter in samples preserved using the agarose-gel microcapsule method compared to samples preserved using the Cryotop method in both the group with sperm concentrations of 1 million/mL or above and the group with sperm concentrations of less than 1 million/mL. This study demonstrated that using the agarose-gel microcapsule method increased post-thawing sperm recovery rate, sperm motility rate, and sperm viability rate, and reduced sperm recovery time compared with the conventional Cryotop method when cryopreserving samples with low sperm count. Although requiring further study, the agarose-gel microcapsule method shows much promise as a new option for freezing sperm.

Glycemic control, including glycemic variability, is important for the prevention of diabetic vascular complications in patients with type 2 diabetes mellitus (T2DM). There was an association between miso soup intake and insulin resistance. However, the relationship between habitual miso consumption and glycemic control, including glycemic variability, in patients with T2DM remains unknown. We defined people without habitual miso consumption if they did not consume miso soup at all in a day. The average, standard deviation (SD), and coefficient of variation (CV), calculated as CV = (SD/average HbA1c) × 100 (%), of hemoglobin (Hb) A1c levels were evaluated. The proportions of habitual miso consumption of male and female were 88.1% and 82.3%, respectively. The average (7.0 [6.4–7.5] vs. 7.3 [6.8–8.4] %, p = 0.009), SD (0.21 [0.12–0.32] vs. 0.37 [0.20–0.72], p = 0.004), and CV (0.03 [0.02–0.04] vs. 0.05 [0.03–0.09], p = 0.005) of HbA1c levels in female with habitual miso consumption were lower than those of female without. Moreover, habitual miso consumption correlated with average (β = −0.251, p = 0.009), SD (β = −0.175, p = 0.016), and CV (β = −0.185, p = 0.022) of HbA1c levels after adjusting for covariates. However, no association between habitual miso consumption and any glycemic parameters was shown among male. This study clarified the association between habitual miso consumption and good glycemic control, including glycemic variability, in female, but not in male.

Background: The aim of this study was to investigate the effect of the coronavirus disease (COVID-19) pandemic restrictions on the change in muscle mass in older patients with type 2 diabetes (T2D), who were not infected with COVID-19. Methods: In this retrospective cohort study, data were obtained from outpatients who underwent bioelectrical impedance analysis at least twice before April 2020 and at least once thereafter. Skeletal muscle mass index (SMI, kg/m2) was calculated as appendicular muscle mass (kg) divided by height squared (m2). Change in SMI (kg/m2/year) was calculated as (follow-up SMI—baseline SMI/follow-up period). The differences between the changes in SMI before and after the start of the COVID-19 pandemic were evaluated using paired t test. Results: This study recruited 56 patients, with a mean (SD) age of 75.2 (7.1) years. SMI changed from 6.7 (0.9) to 6.8 (0.9) kg/m2 before the COVID-19 pandemic, whereas SMI changed from 6.8 (0.9) to 6.6 (0.9) kg/m2 after the start of the COVID-19 pandemic. SMI decreased after the start of the COVID-19 pandemic compared with before the pandemic (−0.117 (0.240) vs. 0.005 (0.289) kg/m2/year, p = 0.049). This decrease was observed in men (−0.159 (0.257) vs. 0.031 (0.325) kg/m2/year, p = 0.038), patients with poor glycemic control (−0.170 (0.264) vs. 0.031 (0.285) kg/m2/year, p = 0.042), and those with a long diabetes duration (−0.153 (0.229) vs. 0.082 (0.291) kg/m2, p = 0.049). Conclusions: The COVID-19 pandemic restrictions caused muscle mass loss in older patents with T2D. Actions, including recommendation of exercise and adequate diet intake, are needed to prevent loss of muscle mass.

It has been reported that oral health is associated with some co-morbid conditions, including cardiovascular disease, in people with type 2 diabetes mellitus. The present study investigated the association between the frequency of toothbrushing and lifestyle in people with type 2 diabetes mellitus. This cross-sectional study included 624 outpatients at the Kyoto Prefectural University of Medicine in Kyoto, Japan from January 2014 to January 2016. Lifestyle was evaluated using a self-administered questionnaire. The average age and hemoglobin A1c level were 67.6 ± 10.9 years and 7.2 ± 1.1%, respectively. The number of patients who brushed their teeth twice or more a day was 189 (50.3%) in men and 198 (79.8%) in women. Among men, the proportion of patients living alone was lower in those who brushed their teeth twice or more a day than those who brushed their teeth never/rarely or once a day. The logistic regression analysis, after adjusting for confounding factors, revealed that living alone (odds ratio 2.88; 95% confidence interval 1.53-5.66) was associated with the increased odds of the low frequency of toothbrushing (never/rarely or once a day) in men, but not in women. In conclusion, the results of our study suggest that living alone was associated with the low frequency of toothbrushing in people with type 2 diabetes mellitus, particularly in men.

Summary Background & aim Past studies reported that the intake of adequate energy is more important than protein intake; however, the relationship between energy intake and muscle mass loss remains unclear thus far. This study therefore explored the association between energy intake and muscle mass loss in people with type 2 diabetes (T2D). Methods In this prospective cohort study, impedance body composition and a brief-type self-administered diet history questionnaire were used for analyzing body composition and habitual diet intake, respectively. Skeletal muscle mass index (SMI, kg/m2) was defined as appendicular muscle mass (kg) ÷ height-squared (m2). Rate of SMI change (%) was calculated as ([SMI at baseline - SMI at follow-up]/[follow-up duration (years) × baseline SMI (kg/m2)]) × 100, and muscle mass loss was defined as rate of SMI change ≥0.5%. Energy intake was defined as total energy intake (kcal/day) divided by ideal body weight (kg), defined as 22 × patient height-squared (m2). Results Among non-older and older participants, 54.8% (n = 51/93) and 58.9% (n = 116/197) experienced muscle mass loss at 16.3 (6.4) and 18.1 (7.1) months’ follow-up, respectively. Logistic regression analyses showed that energy intake was associated with incident muscle mass loss after adjusting for age, sex, insulin, sodium glucose cotransporter-2 inhibitor, glucagon-like peptide-1 agonist, steroids, smoking, exercise, alcohol intake, body mass index, SMI, presence of renal failure, and protein intake (g/actual body weight/day) in the older people (odds ratio [OR] 0.94 [95% confidence interval [CI] 0.88–0.996], p = 0.037), whereas energy intake was not associated with incident muscle mass loss in the non-older people (OR 0.96 [95% CI 0.86–1.06], p = 0.423). Conclusions Insufficient energy intake is associated with muscle mass loss in older people with T2D. Therefore, it is recommended to consume enough energy for older people with T2D to keep muscle mass.

The risk of a gonadal tumor is high in testicular disorder of sexual development (DSD) with the Y chromosome, but cases of DSD without the Y chromosome are extremely rare. We reported a gonadal tumor in a phenotypically male individual with 46, XX testicular DSD. A testicular tumor was incidentally found in a 32-year-old phenotypic male who was presented to the hospital with male infertility. A diagnosis of 46, XX testicular DSD was made by the presentation of karyotype analysis of 46, XX with the sex-determining region of the Y chromosome (SRY) positive and gonadal tissue without female gonads. Surgery was performed due to a gradually growing tumor. The partial orchidectomy was performed with the diagnosis of a benign Leydig cell tumor in frozen biopsy.

To investigate the acute effects of the coronavirus disease 2019 (COVID-19) on the lifestyle and metabolic parameters in patients with type 2 diabetes mellites. This cross-sectional and retrospective cohort study induced 203 patients who completed a questionnaire regarding stress levels and lifestyles. Data regarding stress levels, sleep time, exercise, and total diet, snack, and prepared food intake were obtained from the questionnaires. The changes in the body weight or HbA1c levels were determined by comparing the values at the time the questionnaire was administered to those noted 3 months ago. Increased levels of stress and decreased exercise levels were reported in approximately 40% and >50%. During the COVID-19 pandemic. There was a negative correlation between stress and exercise (r = -0.285, p < 0.001) and a positive correlation between stress and prepared food intake (r = 0.193, p = 0.009). Decreased exercise levels (r = -0.33, p < 0.001) and increased snack consumption (r = 0.24, p = 0.002) were associated with increased body weight. Furthermore, increased total diet intake (r = 0.16, p = 0.031) was associated with increased HbA1c levels. These relationships remained significant for patients aged

Metformin is reported to affect human gut microbiota, however, the nature of this association in Japanese patients with type 2 diabetes mellitus (T2DM) is unknown. We enrolled 31 patients with T2DM who took metformin for the first time in this study. We compared them before and after four weeks of taking metformin. Fecal samples were collected and 16S rDNA sequences were performed to identify the gut microbiota. Blood samples and Gastrointestinal Symptom Rating Scale (GSRS) questionnaire results, denoting gastro-intestinal symptoms, were also collected. In the whole-group analysis, no significant differences were found at the phylum level. In a subgroup of 21 patients that excluding those using medications affecting gut microbiota, there was a significant decrease of the phylum Firmicutes (p = 0.042) and of the ratio of the Firmicutes and Bacteroidetes abundances (p = 0.04) after taking metformin. Changes in abdominal pain (r = &minus, 0.56, p = 0.008) and regurgitation (r = &minus, 0.53, p = 0.01) were associated with Parabacteroides. Despite there being no direct association with abdominal symptoms, our study revealed that the composition of gut microbiota in Japanese individuals with T2DM partially changed after starting metformin.

Aim Diabetes mellitus (DM) is associated with adverse outcomes, and visceral adipose tissue (VAT), classified into intraperitoneal VAT (IVAT) and retroperitoneal VAT (RVAT), is associated with insulin resistance. This study aimed to evaluate the association of IVAT and RVAT with the prevalence or incidence of DM. Methods In this cross-sectional, retrospective, cohort study, the prevalence and incidence of DM was analyzed in 803 and 624 middle-aged Japanese participants, respectively. The cross-sectional area of the abdominal adipose tissue was evaluated from an unenhanced computed tomography scan at the third lumbar vertebrae, and the IVAT or RVAT was analyzed using specialized software. The areas were normalized for the square value of the participants’ height in meters and described as the IVAT or RVAT area index. Results The IVAT area index (adjusted odds ratio [OR], 1.04; 95% confidence intervals [CI], 1.02–1.07, per 1.0 cm2/m2) or IVAT/RVAT area ratio (1.89; 1.23–2.85, per 1.0) was independently associated with the prevalence of DM, whereas the RVAT area index was not. During a follow-up (mean) of 3.7 years, 30 participants were diagnosed with DM. The IVAT area index (adjusted hazards ratio [HR], 1.02; 95% CI 1.003–1.04, per 1.0 cm2/m2) or IVAT/RVAT area ratio (2.25; 1.40–3.43, per 1.0) was independently associated with the incidence of DM, whereas the RVAT area index was not. Conclusions IVAT, but not RVAT, is associated with the prevalence or incidence of DM.

Cardiovascular disease (CVD) is still the major cause of mortality in patients with type 2 diabetes. Despite of recent therapies, mortality and resources spent on healthcare due to CVD is still important problem. Thus, appropriate markers are needed to predict poor outcomes. Therefore, we investigated the role of peripheral perfusion as an indicator for cardiovascular death in patients with type 2 diabetes and established CVD. This retrospective cohort study included 1080 patients with type 2 diabetes and history of CVD recruited from the outpatient clinic at Matsushita Memorial Hospital in Osaka, Japan. Peripheral perfusion is assessed using the perfusion index (PI), which represents the level of circulation through peripheral tissues. The median age and PI values were 74 years (range: 67–79 years) and 2.6% (range: 1.1–4.3%), respectively. During follow-up duration, 60 patients died due to CVD. The adjusted Cox regression analysis demonstrated that the risk of developing cardiovascular death was higher in the first quartile (Hazard ratio, 6.23; 95% CI, 2.28 to 22.12) or second quartile (Hazard ratio, 3.04; 95% CI, 1.46 to 6.85) of PI than that in the highest quartile (fourth quartile) of PI. PI (per 1% decrease) was associated with the development of cardiovascular death (Hazard ratio, 1.39; 95% CI, 1.16 to 1.68). PI could be a novel indicator of cardiovascular death in patients with type 2 diabetes and established CVD.

Non-alcoholic fatty liver disease (NAFLD), often complicated by type 2 diabetes mellitus (T2DM), is reported to be associated with diet habits, including eating speed, in the general population. However, the association between eating speed and NAFLD in patients with T2DM, especially sex difference, has not been reported so far. This cross-sectional study included 149 men and 159 women with T2DM. Eating speed was evaluated by a self-reported questionnaire and divided into three groups: fast, moderate, and slow eating. Nutrition status was evaluated by a brief-type self-administered diet history questionnaire. NAFLD was defined as the hepatic steatosis index &ge, 36 points. Body mass index and carbohydrate/fiber intake in the fast-eating group were higher than those in the slow-eating group in men, whereas this difference was absent in women. In men, compared with eating slowly, eating fast had an elevated risk of the presence of NAFLD after adjusting for covariates (odds ratio (OR) 4.48, 95% confidence interval (CI) 1.09&ndash, 18.5, p = 0.038). In women, this risk was not found, but fiber intake was found to be negatively associated with the presence of NAFLD (OR 0.85, 95% Cl 0.76&ndash, 0.96, p = 0.010). This study indicates that eating speed is associated with the presence of NAFLD in men but not in women.

We investigated the role of peripheral perfusion as an indicator for cardiovascular death in patients with type 2 diabetes and established cardiovascular disease (CVD). This retrospective cohort study included 1080 patients with type 2 diabetes and history of CVD recruited from the outpatient clinic at Matsushita Memorial Hospital in Osaka, Japan. Peripheral perfusion is assessed using the perfusion index (PI), which represents the level of circulation through peripheral tissues. PI was measured using a Masimo SET Radical-7 (Masimo Corporation, Irvine, CA) instrument. The median age and PI values were 74 years (range: 67-79 years) and 2.6% (range: 1.1-4.3%), respectively. The average duration of follow up was 871 ± 265 days. During follow-up duration, 60 patients died due to CVD. The adjusted Cox regression analysis demonstrated that the risk of developing cardiovascular death was higher in the first quartile (HR, 5.84; 95% CI, 2.23 to 20.16) or second quartile (HR, 3.00; 95% CI, 1.05 to 10.81) of PI than that in the highest quartile (fourth quartile) of PI. PI (per 1% decrease) was associated with the development of cardiovascular death (HR, 1.38; 95% CI, 1.15 to 1.64). PI could be a novel indicator of cardiovascular death in patients with type 2 diabetes and established CVD. Disclosure H. Okada: None. Y. Okada: None. M. Fukui: None.

Objective: To examine the association between human papillomavirus (HPV) infection and penile cancer among Japanese patients. Methods: Thirty-four patients with penile cancer were enrolled in this study. DNA was extracted from paraffin-embedded tumor tissue samples, and HPV-DNA tests and genotyping were performed. For all of the samples, in situ hybridization (ISH) was performed to locate HPV-DNA in tumor tissue. Furthermore, expression levels of p16-INK4a, mini-chromosome maintenance protein 7 (mcm-7), HPV-L1, and Ki-67 were analyzed using immunohistochemical methods. Results: HPV and high-risk (HR)-HPV were detected in 14 (41.1%; 95% confidence interval (CI) 24.6–57.7%) and 12 (35.2%; 95% CI 19.2–51.4%) cases, respectively. HPV16 was the most frequently detected HPV type. Among the HR-HPV-positive cases, a punctate HR-HPV-DNA signal pattern was detected by ISH in tumor cell nuclei. P16-INK4a was expressed in 66.7% (95% CI 42.8–90.1%) of HR-HPV-positive cases and was significantly more frequent and stronger in HR-HPV-positive cases than in HPV-negative cases. There was no significant difference in the occurrence or distribution of mcm-7 or Ki-67 expression between HPV-positive and HPV-negative cases. HPV-L1 expression was not observed in any of the cases examined. Conclusions: HPV infection may have had an etiological role in 41% of the examined cases of penile cancer in Japan. Keywords: Penile cancer, Human papillomavirus, p16-INK4a, Mini-chromosome maintenance protein 7, Ki-67

Metabolic syndrome is reported to play a role in the genesis and development not only of angina, arteriosclerosis, diabetes, and osteoporosis but also of prostate cancer. Hypercholesterolemia is a strong risk factor in prostate cancer development. The current study was conducted to analyze whether pretreatment serum levels of cholesterol correlate with prostate cancer metastasis. Three hundred fifty-one subjects who received a histopathological diagnosis of prostate cancer were evaluated by clinical factors such as age, body mass index (BMI), disease stage, Gleason score, prostate-specific antigen (PSA), total cholesterol, Luteinizing hormone (LH), testosterone, and free testosterone. A multivariate analysis was performed on these factors, and a statistically significant difference was identified in total cholesterol level ( p =.01) and PSA ( p < .001). The total cholesterol level was higher in cases of metastatic prostate cancer compared to nonmetastatic prostate cancer in this study and therefore may be a predictive factor for poor prognosis.

The majority of facilities in Japan that offer artificial insemination as part of assisted reproduction programs currently perform semen collection in the early morning. The total motile sperm count of the semen used in intrauterine insemination is an important factor in achieving successful fertilization and subsequent childbirth. The present study was initiated to determine whether semen parameters varied with the time of day at which the semen sample was collected. The study subjects were 20 fertile males and 20 infertile males with abnormal seminograms who attended our Reproduction Center. Semen was collected early in the morning (morning collection group) and in the evening (evening collection group) from the same subjects, and total motile sperm count was assessed as the primary outcome measure. As secondary outcome measures, semen volume, sperm concentration, sperm motility and total sperm count were assessed. A sexual abstinence period of 3 days was set for all participants. The semen samples were analyzed using CASA CEROS, a sperm motility analysis system, and the data from the morning and evening collection groups were compared using a Wilcoxon signed rank test. We found that the fertile males had a significantly higher total motile sperm count and total sperm count in the evening collection group than in the morning collection group. In contrast, the male infertility patients showed no significant difference in total sperm count between the two collection times; however, the total motile sperm count was significantly higher in the evening collection group than the morning collection group. Our analyses indicate that total motile sperm count in ejaculated semen is significantly higher after evening collection than after morning collection. From a male side perspective, we suggest that successful intrauterine insemination might be easier to achieve using semen collected in the evening than in the early morning.

In this study, we aimed to elucidate the association between taste acuity and serum zinc concentration in patients with type 2 diabetes.We enrolled 29 patients who were hospitalized and asked them to attend a 2-week diabetes education program. Fasting blood samples were obtained on the morning of the first day and 2 weeks after hospitalization. The acuity of sweet, salty, sour or bitter taste was evaluated by a filter-paper disc method. Correlations among taste acuity, glycemic control and serum zinc concentration were analyzed using the Spearman rank correlation coefficient.The following parameters (mean ± standard deviation) were improved after 2 weeks' hospitalization: taste acuity (sweet: 3.5±1.0 to 2.9±1.1; salty: 3.3±1.1 to 2.6±1.0; sour: 3.6±1.2 to 2.7±0.8; and bitter: 3.3±1.3 to 2.7±1.1; all p0.001); glycemic control (fasting plasma glucose, 9.4±3.0 to 7.1±1.8 mmol/L, and glycoalbumin, 26.3±7.7 to 22.7±5.9 %; both p0.001); and serum zinc concentration (1.2±0.2 to 1.3±0.2 mmol/L; p0.001). Sour and bitter taste acuity were significantly associated with serum zinc concentration (sour, r=-0.50, p=0.005; bitter, r=-0.40, p=0.033).Glycemic control, serum zinc concentration and taste acuity were improved after the short-duration education program. Sour and bitter taste acuity were significantly associated with serum zinc concentrations.

AIM To investigate the association between sarcopenia and blood pressure parameters in older patients with type 2 diabetes. METHODS This was a cross-sectional study of 146 older patients with diabetes. Body composition was evaluated by bioimpedance analysis. The skeletal muscle mass index (kg/m2 ) was defined as appendicular muscle mass / the square of the height. Patients with both handgrip strength

The American Society of Clinical Oncology (ASCO) Clinical Practice guidelines recommend that physicians, nurses, social workers, and other health care providers should be prepared to discuss the risk of infertility with patients. We conducted an educational program for non-physician health care providers regarding fertility preservation and evaluated the effects of the educational program. The 4-h educational program consisted of lectures about infertility as a potential risk of cancer treatment, fertility preservation, and psychosocial support. Knowledge, confidence, institutional change, and self-practice were assessed pre-program, immediately post-program, and 6 months post-program. Of 124 participants who joined the program, 74 completed and returned the follow-up survey 6 months after the program. Sixty-one percent of the participants were nurses, 27% were social workers, and 4% were psychologists. The scores for confidence and knowledge increased between pre- and immediate post-program periods (p

The aim of this cross-sectional study was to examine the association between the geriatric nutritional risk index (GNRI) and the prevalence of sarcopenia in people with type 2 diabetes (T2DM). Having both low handgrip strength (&lt, 28 kg for men and &lt, 18 kg for women) and low skeletal muscle mass index (&lt, 7.0 kg/m2 for men and &lt, 5.7 kg/m2 for women) was diagnosed as sarcopenia. GNRI was estimated by the formula as below: GNRI = (1.489 × serum albumin level [g/L]) + (41.7 × [current body weight (kg)/ideal body weight (kg)]). Participants were dichotomized on the basis of their GNRI scores (GNRI &lt, 98, low, or GNRI ≥ 98, high). Among 526 people (301 men and 225 women) with T2DM, the proportions of participants with sarcopenia and low GNRI were 12.7% (n = 67/526) and 5.1% (n = 27/526), respectively. The proportion of sarcopenia in participants with low-GNRI was higher than that with high GNRI (44.4% [n = 12/27] vs. 11.0% [n = 55/499], p &lt, 0.001). The GNRI showed positive correlations with handgrip strength (r = 0.232, p &lt, 0.001) and skeletal muscle mass index (r = 0.514, p &lt, 0.001). Moreover, low GNRI was related to the prevalence of sarcopenia (adjusted odds ratio, 4.88 [95% confidence interval: 1.88–12.7], p = 0.001). The GNRI, as a continuous variable, was also related to the prevalence of sarcopenia (adjusted odds ratio, 0.89 [95% confidence interval: 0.86–0.93], p &lt, 0.001). The present study revealed that low GNRI was related to the prevalence of sarcopenia.

To analyse the quantitative changes of the prostate and seminal vesicles (SV) on magnetic resonance imaging (MRI) after ejaculation. Ten healthy young males were enrolled for T2-weighted and T2 mapping MRI before and after two consecutive ejaculations. T2 values of the peripheral zone (PZ) and the central gland (CG) at the midgland of the prostate were compared before and after ejaculation, respectively. T2 values of the PZ at the apex and base were also compared before and after, respectively. Pre- and post-ejaculation SV volumes were compared. The Wilcoxon’s signed rank test with Bonferroni adjustment was used for comparison. After ejaculation, T2 values of the PZ significantly decreased (mean, 119±20 vs. 105±21, p=0.002) while those of the CG did not significantly change at the midgland. At the apex, T2 values of the PZ also decreased significantly (mean, 114±9 vs. 94±7, p=0.002). On the other hand, T2 values of the PZ did not change at the base. SV volumes were significantly reduced after ejaculation (mean, 11.1±7.7mL vs. 7.2±6.7mL, p=0.002). Ejaculation decreases T2 values of the PZ at the midgland and apex, and reduces SV volumes. Abstinence periods should be considered in evaluating the prostate and SV on MRI. • T2 values decrease after ejaculation in the apical-mid peripheral zone. • Ejaculation does not affect T2 values of the central gland. • Volume of the seminal vesicles decreases after ejaculation. • An abstinence period should be considered before pelvic MRI in men.

Azoospermia affects up to 1% of adult men. Non-obstructive azoospermia is a multifactorial disorder whose molecular basis remains largely unknown. To date, mutations in several genes and multiple submicroscopic copy-number variations (CNVs) have been identified in patients with non-obstructive azoospermia. The aim of this study was to clarify the contribution of nucleotide substitutions in known causative genes and submicroscopic CNVs in the genome to the development of non-obstructive azoospermia. To this end, we conducted sequence analysis of 25 known disease-associated genes using next-generation sequencing and genome-wide copy-number analysis using array-based comparative genomic hybridization. We studied 40 Japanese patients with idiopathic non-obstructive azoospermia. Functional significance of molecular alterations was assessed by in silico analyses. As a result, we identified four putative pathogenic mutations, four rare polymorphisms possibly associated with disease risk, and four probable neutral variants in 10 patients. These sequence alterations included a heterozygous splice site mutation in SOHLH1 and a hemizygous missense substitution in TEX11, which have been reported as causes of non-obstructive azoospermia. Copy-number analysis detected five X chromosomal or autosomal CNVs of unknown clinical significance, in addition to one known pathogenic Y chromosomal microduplication. Five patients carried multiple molecular alterations. The results indicate that monogenic and oligogenic mutations, including those in SOHLH1 and TEX11, account for more than 10% of cases of idiopathic non-obstructive azoospermia. Furthermore, this study suggests possible contributions of substitutions in various genes as well as submicroscopic CNVs on the X chromosome and autosomes to non-obstructive azoospermia, which require further validation.