Combined effect of histological findings and diabetes mellitus on liver-related events in patients with metabolic dysfunction-associated steatotic liver disease.

AIM: Advanced fibrosis has a strong influence on the occurrence of liver-related events in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), while diabetes mellitus (DM), which is often complicated by MASLD, is associated with the progression of MASLD. We stratified patients with MASLD according to the severity of liver pathological findings and the presence of DM, aiming to examine whether these indices could be used to accurately assess the risk of developing liver-related events. METHODS: A total of 282 patients with liver biopsy-proven MASLD were included. Liver-related events were defined as the occurrence of hepatocellular carcinoma (HCC) and complications of liver cirrhosis, such as ascites, hepatic encephalopathy, Child-Pugh class B and C, as well as treatment-eligible esophageal and gastric varices. RESULTS: Multivariate analysis adjusted for age, sex, body mass index, alanine aminotransferase, creatinine, hemoglobin A1c, smoking habits, dyslipidemia, hypertension, nonalcoholic fatty liver disease activity score (NAS), or fibrosis stage showed that advanced fibrosis with or without DM was a risk factor for liver-related events. The combined effect of DM and advanced fibrosis increased the risk of HCC onset. However, DM alone or in combination with NAS did not affect the development of liver-related events, including the occurrence of HCC and complications of liver cirrhosis. CONCLUSIONS: While the assessment of fibrosis in patients with MASLD is important for evaluating the risk of developing liver-related events, combining the assessment of DM may be possible to stratify groups at higher risk of developing HCC.

Coffee and caffeine intake reduces risk of ulcerative colitis: a case-control study in Japan.

BACKGROUND AND AIM: Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC. METHODS: The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy. RESULTS: Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001). CONCLUSIONS: We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries.

Serum albumin levels as a useful complementary marker for erectile dysfunction in ulcerative colitis: A cross-sectional study.

OBJECTIVE: Recently, a close association between ulcerative colitis (UC) and erectile dysfunction (ED) was reported. An inverse relationship between serum albumin and ED is found in patients with chronic disease. However, the association between serum albumin levels and ED in patients with UC is unclear. This study aims to investigate this issue in Japanese patients with UC. METHODS: One hundred and thirty-six Japanese male UC patients were enrolled in this study. Information on serum albumin levels and medications for UC from medical records, Sexual Health Inventory for Men (SHIM) score information from self-administered questionnaires and information on the severity of UC from physician reports were obtained from medical records, self-administered questionnaires, and reports from physicians. The participants were divided into tertiles based on the total protein, serum globulin, serum albumin, aspartate aminotransferase, and C-reactive protein levels. The definition of ED and severe ED was SHIM score < 22 and SHIM score < 8, respectively. The association between these serum markers and ED was assessed by multivariate logistic regression. RESULTS: The prevalence of severe ED in the low, moderate, and high albumin groups was 66.0%, 51.0%, and 28.3%, respectively. After adjusting for confounding factors, the low albumin group was independently and positively associated with severe ED (adjusted odds ratio: 2.74, 95% confidence interval: 1.03-7.48, p for trend =0.044). No association between other marker and ED was found. CONCLUSION: Serum albumin was independently inversely associated with severe ED in Japanese patients with UC. Hypoalbuminemia might be a useful complementary marker for assessing the prevalence and severity of ED in UC patients.

Menstrual Status Is Associated with the Prevalence of Irritable Bowel Syndrome in a Japanese Young Population: A Cross-Sectional Study.

INTRODUCTION: There is evidence regarding the association between dysmenorrhea and irritable bowel syndrome (IBS), although it is lacking in the Asian population. Therefore, the purpose of this study was to investigate the association between menstrual status and IBS in a young Japanese. METHODS: Overall, 4,693 female college students were included in the analysis of this study. Information regarding lifestyle habits, menstrual status (irregularity, pain severity, and medication), and IBS (Rome III criteria) was obtained using a self-reported questionnaire. Age, body mass index, exercise habits, smoking, drinking habits, and anemia were analyzed as potential confounders. RESULTS: The prevalence of IBS was 6.1%. Moderate {adjusted odds ratio (OR): 1.89 (95% confidence interval [CI]: 1.27-2.91)} and heavy (adjusted OR: 2.14 [95% CI: 1.42-3.45]) menstrual pain were independently positively associated with IBS (p for trend = 0.001). Using medication sometimes (adjusted OR: 1.41 [95% CI: 1.09-1.84]) and often (adjusted OR: 1.60 [95% CI: 1.13-2.24]) was independently positively associated with IBS. There was no association between menstrual cycle and IBS. In subjects without functional dyspepsia, irregular menstrual cycle was independently positively associated with IBS. CONCLUSION: In the young Japanese population, menstrual pain and medications for menstrual pain may have a significant positive association with IBS.

Intranasal therapeutic vaccine containing HBsAg and HBcAg for patients with chronic hepatitis B; 18 months follow-up results of phase IIa clinical study.

AIMS: HBsAg loss with anti-HBs acquisition is considered a functional cure and ideal treatment goal for patients with CHB. Our group have reported the efficacy of therapeutic vaccine with HBsAg and HBcAg (NASVAC) by intranasal and subcutaneous injection. In this study, we investigated the safety and efficacy of newly developed CVP-NASVAC, which contained NASVAC with mucoadhesive carboxyl vinyl polymer (CVP) in the dedicated device. METHODS: A single dose, open-label, phase IIa clinical trial of CVP-NASVAC was conducted. Patients with CHB treated with nucleoside/nucleotide analogs (NAs) and HBV carriers not undergoing anti-HBV treatment were enrolled. CVP-NASVAC was injected through the nose for, in total, 10 times. Participants were followed-up for 18 months, and their HBsAg reduction and anti-HBs induction assessed as endpoints. RESULTS: Among the patients with CHB treated with NAs (n = 27) and HBV carriers without NAs (n = 36), 74.1% and 75.0% exhibited reductions in their baseline HBsAg, and the mean reductions were -0.1454 log10  IU/ml (p < 0.05) and -0.2677 log10  IU/ml (p < 0.05), respectively. Anti-HBs antibody was detected in 40.7% and 58.3% of patients treated with and without NAs, respectively. Six of 71 (9.5%) patients were functionally cured after the CVP-NASVAC treatment. CONCLUSIONS: Anti-HBs induction and HBsAg reduction was observed after CVP-NASVAC treatment in some patients with CHB. The CVP-NASVAC is a safe treatment, which might expect to achieve functional cure for patients with CHB.

Association of abnormal glucose tolerance with liver-related disease and cardiovascular diseases in patients with chronic hepatitis C.

AIM: Hepatitis C complicated by diabetes mellitus (DM) is considered a risk factor for the progression of fibrosis and development of hepatocellular carcinoma (HCC) and cardiovascular diseases. However, several studies may have lacked appropriate diagnosis of glucose intolerance. We aimed to examine the risk associated with abnormal glucose intolerance in the development of liver-related diseases, including HCC and complications of liver cirrhosis, such as ascites, esophageal and gastric varices, and hepatic encephalopathy, and cardiovascular diseases in patients with hepatitis C accurately diagnosed with impaired glucose tolerance. METHODS: This longitudinal retrospective study included 365 patients with chronic hepatitis C admitted to Ehime University Hospital for anti-hepatitis C therapy between September 1991 and January 2015. Patients were classified into normal glucose tolerance (NGT), prediabetes, and DM groups based on 75-g oral glucose tolerance test results. RESULTS: Both univariate and multivariate (adjusted for potential confounders) analyses revealed a significantly higher risk of developing HCC and cardiovascular events in the DM group than in the NGT group. However, in multivariate analysis, liver-related events, particularly liver cirrhosis complications, revealed no significant association. In addition, the prediabetes group had no significant risk of any outcome. CONCLUSIONS: Patients with hepatitis C complicated by DM, compared with patients with hepatitis C with NGT or complicated with prediabetes, have a higher risk of HCC and cardiovascular disease events, but not liver-related events, particularly in not developing liver cirrhosis complications. Therefore, appropriate follow-up is required for patients with hepatitis C based on their glucose tolerance status.

Association between Mucosal Healing and Lipid Profiles in Patients with Ulcerative Colitis: A Cross-Sectional Study.

INTRODUCTION: Recent meta-analysis showed that ulcerative colitis (UC) is a risk factor for cardiovascular disease (CVD). Dyslipidemia is a well-established risk factor for CVD. However, evidence regarding inflammatory bowel disease (IBD), including UC and lipid profiles, is limited. Additionally, no study has assessed the association between endoscopic activity and lipid profiles in patients with IBD. Therefore, we aimed to clarify the association between mucosal healing (MH) and lipid profiles in patients with UC. METHODS: A total of 221 Japanese patients with UC were enrolled in this analysis. Total cholesterol (T-chol), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) were divided into tertiles (high, moderate, and low) based on the distributions, respectively. Self-administered questionnaire was used to obtain information regarding medication for dyslipidemia. Complete MH and MH are based on Mayo endoscopic subscore 0 and 0-1, respectively. RESULTS: The percentage of complete MH was 30.8%. In patients without medication for dyslipidemia, high HDL-C (>66 mg/dL) was significantly positively associated with complete MH (adjusted odds ratio [OR] 2.58, 95% CI: 1.04-6.64, p for trend = 0.037). In patients with nonproctitis, a positive association between HDL-C and complete MH was found (adjusted OR 3.54, 95% CI: 1.22-11.01, p for trend = 0.020). T-chol and TG were not associated with MH, regardless of medication for dyslipidemia. CONCLUSIONS: Complete MH was significantly positively associated with HDL-C in UC patients without medication for lipid. The disease extent might affect the association between complete MH and HDL-C.

Role of B Cell-Activating Factor in Fibrosis Progression in a Murine Model of Non-Alcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease all over the world. Therapeutic strategies targeting its multidirectional pathways are required. Particularly, fibrosis is closely associated with its prognosis. We previously found that B cell-activating factor (BAFF) is associated with severity of NAFLD. Here, we determined the direct in vivo role of BAFF in the development of liver fibrosis. Histological and biochemical analyses were performed using wild-type and BAFF-deficient mice. We established a murine model of non-alcoholic steatohepatitis (NASH) using carbon tetrachloride injection accompanied by high-fat/high-cholesterol diet feeding. Additionally, in vitro analysis using mouse macrophage-like cell line RAW264.7 and primary hepatic stellate cells was performed. Hepatic steatosis and inflammation, and most importantly, the progression of liver fibrosis, were ameliorated in BAFF-deficient mice compared to those wild-type mice in our model. Additionally, BAFF deficiency reduced the number of CD11c+ M1-type macrophages in the liver. Moreover, BAFF stimulated RAW264.7 cells to secrete nitric oxide and tumor necrosis factor α, which drove the activation of hepatic stellate cells. This indicates that BAFF plays a crucial role in NASH development and may be a promising therapeutic target for NASH.

IL12B rs6887695 polymorphism and interaction with alcohol intake in the risk of ulcerative colitis in Japan.

BACKGROUND: The interleukin (IL)-23/Th17 pathway plays a critical role in ulcerative colitis (UC). The IL-12p40 subunit, which is shared by IL-23 and IL-12, is encoded by the IL12B gene. The current case-control study investigated the association between IL12B SNP rs6887695 and the UC risk. METHODS: There were 384 cases within 4 years of UC diagnosis and 661 controls who were enrolled. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. RESULTS: Subjects with the GG IL12B SNP rs6887695 genotype had a significantly increased risk of UC compared with those with the CC genotype (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.08-2.36). This positive association was also significant using the additive and recessive models (AOR, 1.25; 95% CI, 1.03-1.52; AOR, 1.50; 95% CI, 1.08-2.09, respectively). An independent inverse relationship was observed between ever alcohol consumption and the UC risk in those with the CC genotype while no significant association was found in those with at least one G allele (P for interaction = 0.0008). CONCLUSIONS: IL12B SNP rs6887695 was significantly associated with UC. The influence of alcohol consumption might rely on rs6887695.

Association between clinical outcomes and restless legs syndrome in Japanese patients with ulcerative colitis.

Restless legs syndrome (RLS) is a common sleep disorder in the Western population. The prevalence of restless legs syndrome in the Japanese population is 4.6%. Inflammatory and/or immune alteration might be associated with the development of restless legs syndrome. Ulcerative colitis is a chronic inflammatory bowel disease. Evidence regarding the association between ulcerative colitis and the prevalence of restless legs syndrome is limited. Herein, we investigated the association between clinical outcomes and the prevalence of restless legs syndrome in Japanese patients with ulcerative colitis. This was a cross-sectional study using baseline data from a prospective cohort study. Subjects in this study were 273 patients with ulcerative colitis. The definition of restless legs syndrome was achieved using a self-administered questionnaire based on the diagnostic criteria for restless legs syndrome in an epidemiological study approved by the Executive Committee of the International Restless Leg Syndrome Study Group in 2002. Clinical outcomes were clinical remission and mucosal healing. The association between clinical remission and mucosal healing and the prevalence of restless legs syndrome was assessed by multivariate logistic regression analyses. The percentage of clinical remission and mucosal healing was 58.4% and 63.1%, respectively. The prevalence of restless legs syndrome in this cohort was 4.7%. Clinical remission (adjusted odds ratio 0.23, 95% confidence interval 0.05-0.93) and mucosal healing (adjusted odds ratio 0.23, 95% confidence interval 0.05-0.90) were independently inversely associated with restless legs syndrome. No association between serum haemoglobin and restless legs syndrome was found. In conclusion, clinical remission and mucosal healing were independently and inversely associated with the prevalence of restless legs syndrome in Japanese patients with ulcerative colitis.

Effect of disease duration on the association between C-reactive protein-albumin ratio and endoscopic activity in ulcerative colitis.

BACKGROUND: A simple serum biomarker for clinical outcome in patients with ulcerative colitis (UC) remains an unmet need. Some studies have shown an association between C-reactive protein (CRP)-albumin ratio (CAR) and prognosis in patients with inflammatory bowel disease (IBD), but evidence regarding the association between CAR and UC remains limited. We evaluated the association between CAR and clinical outcome in Japanese patients with UC. METHODS: Subjects were 273 Japanese patients with UC. Clinical remission was defined as absence of both abnormally high stool frequency (< 3 per day) and rectal bleeding. Mucosal healing (MH) was defined as Mayo endoscopic subscore (MES) 0. Moderate to severe endoscopic activity was defined as MES 2-3. Subjects were divided according to CAR into tertiles (low, moderate, and high). RESULTS: The proportions of patients with clinical remission, MH, and moderate to severe endoscopic activity were 57.9%, 26.0%, and 37.0%, respectively. High CAR was significantly positively associated with moderate to severe endoscopic activity but not MH or clinical remission after adjustment (adjusted odds ratio [OR] 2.18 [95% confidence interval (CI) (1.11-4.35)], p for trend 0.023), but only in patients with long disease duration (> 7 years) (adjusted OR 2.95 [95% CI (1.06-8.79)], p for trend 0.023). CAR was not associated with clinical remission or MH. CONCLUSIONS: CAR may be significantly positively associated with moderate to severe endoscopic activity but not clinical remission or MH in Japanese patients with UC. In patients with long UC duration, CAR might be a useful serum marker for disease activity.

Association between body mass index and irritable bowel syndrome in the young Japanese population: a cross-sectional study.

PURPOSE: The association between body mass index (BMI) and irritable bowel syndrome (IBS) has been inconsistent in the Asian population. Also, no evidence regarding this issue in the young population exists. The aim of the present study is to investigate the association between BMI and IBS based on the Rome III criteria in young Japanese people. METHODS: This study was a cross-sectional study consisted of 8923 Japanese university students. The definition of IBS was based on the Rome III criteria. BMI was divided into four categories (quartiles) on the basis of the study subjects' distribution (lowest, low, moderate, and high [reference]). The definition of lean, normal, and overweight was BMI < 18.5 kg/m2, 18.5 ≤ BMI < 25 kg/m2 (reference), and 25 ≤ BMI kg/m2, respectively. Age, sex, drinking, smoking, exercise habit, anemia, and sports injury were selected a priori as potential confounding factors. RESULTS: The prevalence of IBS was 6.5%, with females having a significantly higher prevalence than males (6.0% vs. 7.2%, p = 0.029). In females, being overweight was independently positively associated with IBS after adjustment (adjusted odds ratio [OR]: 1.81 [95% confidence interval (CI): 1.13-2.79]). In contrast, in males, no association between being lean or overweight and IBS was found. CONCLUSIONS: Among the young Japanese population, being overweight might be independently positively associated with prevalence of IBS in females but not in males.

Active and passive smoking and risk of ulcerative colitis: A case-control study in Japan.

BACKGROUND AND AIM: Although an inverse relationship between current smoking and the development of ulcerative colitis (UC) has been shown in North America and Europe, evidence is limited in Asian countries, where the incidence of UC is rapidly increasing. This Japanese case-control study examined the association between active and passive smoking and risk of UC. METHODS: A self-administered questionnaire was used to obtain information on smoking and potential confounding factors in 384 cases with a diagnosis of UC within the past 4 years and 665 controls. RESULTS: Compared with having never smoked, having ever smoked was associated with an increased risk of UC (adjusted odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.23-2.37). No association was observed between current smoking and risk of UC, but former smokers had a significant elevation in risk (adjusted OR = 2.40, 95% CI: 1.67-3.45). There was a positive dose-response relationship with pack-years smoked (P for trend = 0.006). Among never smokers, passive smoking exposure at home was significantly associated with an increased risk of UC (adjusted OR = 1.90, 95% CI: 1.30-2.79). A significant dose-response gradient was also observed between pack-years of passive smoking at home and risk of UC (P for trend = 0.0003). CONCLUSIONS: We confirmed that former smoking elevated the risk of UC, whereas an inverse association between current smoking and the risk of UC did not reach a statistically significant level. Passive smoking may be associated with an increased risk of UC.

Positive Association Between Sleep Disturbance and Prevalence of Functional Dyspepsia in Japanese Young People.

BACKGROUND: Evidence regarding the association between sleep disturbance and functional dyspepsia (FD) remains limited in the young population. AIMS: This study aimed to investigate the association between sleep disturbance and FD including subgroups among Japanese young people. METHODS: Study subjects were 8923 university students. FD was defined according to the Rome III criteria. Subjects with FD were further categorized as having postprandial distress syndrome (PDS) or epigastric pain syndrome (EPS). Subjects completed a self-reported questionnaire assessing self-reported sleep duration, sleep disturbance, difficulty falling asleep, deep sleep disorder, nocturnal awakening, early awakening, and daytime sleepiness. RESULTS: The prevalence of FD was 1.9%. After adjustment, all types of sleep disturbances were independently positively associated with FD (total sleep disturbance: OR 4.11 [95% CI: 2.89-5.78], difficulty falling asleep: OR 3.97 [95% CI: 2.53-6.01], deep sleep disorder: OR 4.85 [95% CI: 3.06-7.40], nocturnal awakening: OR 4.35 [95% CI: 1.90-8.67], early awakening: OR 4.50 [95% CI: 1.97-8.97], and daytime sleepiness: OR 2.83 [95% CI: 1.25-5.56]). While nocturnal awakening and daytime sleepiness were not associated with EPS, the other types of sleep disturbance were independently positively associated with EPS and PDS. No association between self-reported sleep duration and FD was found. CONCLUSIONS: Sleep disturbance may be independently positively associated with the prevalence of FD among Japanese young people. Nocturnal awakening and daytime sleepiness were not associated with EPS; the other types of sleep disturbance were independently positively associated with EPS and PDS.

Relationship between body composition and the histology of non-alcoholic fatty liver disease: a cross-sectional study.

BACKGROUND: Causes of non-alcoholic fatty liver disease and its progression include visceral fat accumulation and loss of muscle mass; however, which of the two phenomena is more critical is unclear. Therefore, we intended to examine the relationship between body composition and non-alcoholic fatty liver disease progression as indicated by fibrosis and the non-alcoholic fatty liver disease activity score. METHODS: This cross-sectional study comprised 149 patients (55 men; age, 20-76 years) treated for non-alcoholic fatty liver disease between December 2010 and January 2020. Body composition measurements, histological examinations of liver samples, and comprehensive blood chemistry tests were performed. The relationship between body composition and non-alcoholic fatty liver disease histology findings was analyzed using the logistic regression model. RESULTS: Fibrosis was significantly and inversely correlated with muscle mass and appendicular skeletal muscle mass and significantly and positively correlated with fat mass, fat mass/height squared, visceral fat area, and waist-hip ratio (P < 0.05). After adjustment for sex, blood chemistry measurements, and body composition indices, fibrosis remained associated with appendicular skeletal muscle mass, fat mass, fat mass/height squared, and visceral fat area (P < 0.05). Non-alcoholic fatty liver disease activity score ≥ 5 significantly correlated with fat mass and fat mass/height squared in a univariate but not multivariate analysis. CONCLUSIONS: Fibrosis in non-alcoholic fatty liver disease, an indicator of unfavorable long-term outcomes, is associated with more indices of fat mass than of those of muscle mass. Hence, fat mass should be controlled to prevent non-alcoholic fatty liver disease progression.

Clinical effectiveness of switching between DPP-4 inhibitors in patients with type 2 diabetes mellitus
.

OBJECTIVES: Dipeptidyl peptidase-4 inhibitors (DPP-4Is) can be classified into three categories according to their binding subsites. We wished to clarify the efficacy of switching between DPP-4Is according to their binding subsites. MATERIALS AND METHODS: We undertook a retrospective study of the medical records of patients who switched from one DPP-4I to another. RESULTS: Among 62 patients eligible for study inclusion, the mean change in the glycated hemoglobin (HbA1c) level between different categories of DPP-4I was -0.35 (95% CI, -0.12 to -0.58; n = 59). The mean change in the HbA1c level between each class of DPP-4I was calculated. From class 3 to class 2 it was -0.45 (n = 25); from class 3 to class 1 it was -0.36 (n = 17); from class 1 to class 2 it was -0.24 (n = 7); from class 1 to class 3 it was 0.33 (n = 4); from class 2 to class 1 it was -0.30 (n = 5); from class 2 to class 3 it was -1.30 (n = 1). CONCLUSIONS: When switching DPP-4Is because of insufficient efficacy, consideration of their DPP-4 binding site may be beneficial.

Lenvatinib-induced thyroid abnormalities in unresectable hepatocellular carcinoma.

Lenvatinib has anti-tumor activity against advanced hepatocellular carcinoma (HCC). Hypothyroidism is also a frequent complication in patients treated with lenvatinib. However, studies on lenvatinib-induced thyroid toxicity and destructive thyroiditis are limited. Therefore, this study aimed to clarify the frequency and timing of thyroid abnormalities in lenvatinib for unresectable HCC. This retrospective study enrolled 50 patients with advanced HCC treated with lenvatinib. Patients were classified to have euthyroid, subclinical hypothyroidism, overt hypothyroidism, and thyrotoxicosis. The timing of thyroid dysfunction was assessed, and risk factors for incident hypothyroidism or thyrotoxicosis were evaluated using multivariate models. Subclinical hypothyroidism, overt hypothyroidism, and thyrotoxicosis occurred in 7 (14.0%), 26 (52.0%), and 5 (10.0%) patients, respectively. In the 33 patients with hypothyroidism, 27 (84.4%) developed the condition within 2 weeks of starting lenvatinib treatment. Of the 5 patients with thyrotoxicosis, 3 developed the condition within 8 weeks of starting lenvatinib administration. One patient developed thyrotoxicosis in only 1 week of the initiation of treatment. No correlation between the presence of antibodies and the incidence and severity of thyroid dysfunction due to the autoimmune mechanism was observed. The progression-free survival was significantly better in the hypothyroidism group. Lenvatinib treatment for unresectable HCC not only causes hypothyroidism, but also thyrotoxicosis. Moreover, these thyroid conditions develop within the early period of treatment at a higher prevalence. Patients with thyroid dysfunction had better prognosis. Based on these results, in patients administered with lenvatinib, there is need for careful assessment for the possibility of thyroid dysfunction from the onset of treatment.

Effects of Motilin Receptor Agonists and Ghrelin in Human motilin receptor Transgenic Mice.

Gastrointestinal motility is regulated by neural factors and humoral factors. Both motilin and ghrelin improve gastrointestinal motility, but many issues remain unclear. We prepared human motilin receptor transgenic (Tg) mice and performed experiments evaluating the effects of motilin, erythromycin (EM), and ghrelin. EM and ghrelin promoted gastric emptying (GE) when administered either peripherally or centrally to Tg mice. Atropine (a muscarinic receptor antagonist) counteracted GE induced by centrally administered EM, but not that induced by peripherally administered EM. The administration of EM in this model promoted the effect of mosapride (a selective serotonin 5-hydroxytryptamine 4 (5-HT4) receptor agonist), and improved loperamide (a µ-opioid receptor agonist)-induced gastroparesis. The level of acyl-ghrelin was significantly attenuated by EM administration. Thus, we have established an animal model appropriate for the evaluation of motilin receptor agonists. These data and the model are expected to facilitate the identification of novel compounds with clinical potential for relieving symptoms of dyspepsia and gastroparesis.

The effectiveness of dapagliflozin for sleep-disordered breathing among Japanese patients with obesity and type 2 diabetes mellitus.

Weight reduction is important in patients with sleep-disordered breathing (SDB). In Japanese patients, slight weight reduction is effective for improving the severity of SDB. However, the effect of weight reduction after administration of sodium glucose co-transporter 2 (SGLT2) inhibitor for SDB remains unclear. The aim of this study was to evaluate the improvement of SDB from baseline after administration of dapagliflozin (5 mg) once daily for 24 weeks among Japanese patients with obesity and type 2 diabetes mellitus. Thirty Japanese patients with type 2 diabetes mellitus and SDB were enrolled in a 24-week, prospective, open-label, single-arm, multicentre trial. SDB was defined as at least five 3% oxygen desaturation index (ODI) events per hour, and moderate to severe SDB was defined as at least 15 ODI events per hour. The primary endpoint was the change in 3% ODI between before dapagliflozin administration and at 24 weeks. The prevalence of moderate to severe SDB was 20% in the present study. After administration of dapagliflozin, fasting glucose, HbA1c, aspartate aminotransferase, total cholesterol, low-density lipoprotein cholesterol, and estimated globular filtration rate decreased significantly. The improvement of 3% ODI was observed in patients with moderate to severe SDB but not mild SDB (from 25.0 ± 3.8 at baseline to 18.5 ± 6.1 at 24 weeks, p = 0.017). In conclusion, dapagliflozin might improve moderate to severe SDB but not mild SDB in Japanese patients with obesity and type 2 diabetes mellitus.

Smoking and prevalence of nocturia in Japanese patients with type 2 diabetes mellitus: a post-hoc analysis of The Dogo Study.

AIMS: No evidence exists regarding the association between smoking status and nocturia among patients with type 2 diabetes mellitus. We evaluated this association among Japanese patients with type 2 diabetes mellitus by post-hoc analysis. METHODS: Study subjects were 817 Japanese patients with type 2 diabetes mellitus. Study subjects were considered to have nocturia if they answered "once or more" to the question: "Within one week, how many times do you typically wake up to urinate from sleeping at night until waking in the morning?" We used the following three outcomes: (1) nocturia was ≥1 voids per night; (2) moderate nocturia was ≥2 voids per night; and (3) severe nocturia was ≥3 voids per night. Adjustments were made for age, sex, body mass index, hypertension, dyslipidemia, stroke, glycated hemoglobin, current drinking, use of anti-hypertensive agent, use of insulin, use of oral anti-hyperglycemic agent, and diabetic retinopathy. RESULTS: The prevalence values of one void per night, two voids per night, and three or more voids per night were 39.5%, 27.1%, and 14.8%, respectively. Current smoking was independently inversely associated with severe nocturia compared with never or former smoking; the adjusted PR was 0.47 (95%CI: 0.25-0.89). Among the 443 patients who had ever smoked, compared with former smoking, current smoking was independently inversely related to severe nocturia; the adjusted PR was 0.44 (95%CI: 0.24-0.82). CONCLUSIONS: In Japanese patients with type 2 diabetes mellitus, current smoking may be independently inversely associated with severe nocturia.