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The LRP5 gene encodes a Wnt signaling receptor to which Wnt binds directly. In humans, pathogenic monoallelic variants in LRP5 have been associated with increased bone density and exudative vitreoretinopathy. In mice, LRP5 plays a role in tooth development, including periodontal tissue stability and cementum formation. Here, we report a 14-year-old patient with a de novo non-synonymous variant, p.(Val1245Met), in LRP5 who exhibited mildly reduced bone density and mild exudative vitreoretinopathy together with a previously unreported phenotype consisting of dental abnormalities that included fork-like small incisors with short roots and an anterior open bite, molars with a single root, and severe taurodontism. In that exudative vitreoretinopathy has been reported to be associated with heterozygous loss-of-function variants of LRP5 and that our patient reported here with the p.(Val1245Met) variant had mild exudative vitreoretinopathy, the variant can be considered as an incomplete loss-of-function variant. Alternatively, the p.(Val1245Met) variant can be considered as exerting a dominant-negative effect, as no patients with truncating LRP5 variants and exudative vitreoretinopathy have been reported to exhibit dental anomalies. The documentation of dental anomalies in the presently reported patient strongly supports the notion that LRP5 plays a critical role in odontogenesis in humans, similar to its role in mice.

Objective The aim of this study was to evaluate the long-term outcomes that were the secondary endpoints of a RCT of multi-port laparoscopic colectomy (MPC) versus SILC in colon cancer surgery. Summary of background data The actual long-term outcomes, such as the 5-year RFS, OS, and recurrence patterns after surgery, have not been evaluated by a RCT. Methods Patients with histologically proven colon carcinoma located in the cecum, ascending, sigmoid or rectosigmoid colon clinically diagnosed as stage 0-III were eligible for this study. Patients were preoperatively randomized and underwent complete mesocolic excision. The 5-year RFS, OS, and recurrence patterns were analyzed (UMIN-CTR 000007220). Results Between March 1, 2012, and March 31, 2015, a total of 200 patients were randomly assigned to either the MPC arm (n = 100) or SILC arm (n = 100). The median follow-up for all patients was 61.0 months. An intention-to-treat analysis showed that the 5-year RFS was 91.0% [95% confidence interval (CI) 85.1%-96.9%] in the MPC arm and 88.0% (95% CI 82.1%-93.9%) in the SILC arm (hazard ratio: 1.37; 95% CI 0.58-3.24; P = 0.479). The 5-year OS was 95.0% (95% CI 91.1%-98.9%) in the MPC arm and 93.0% (87.1%-98.9%) in the SILC arm (hazard ratio: 1.39; 95% CI 0.44-4.39; P = 0.568). There were no significant differences in the recurrence patterns between the 2 arms. Conclusions Even though the results of the 5-year OS and RFS in this trial were exploratory and underpowered, there were no statistically significant differences between the SILC and MPC arms. SILC may be an acceptable treatment option for select patients with colon cancer.

The diagnosis of strangulated bowel obstruction (SBO) is sometimes difficult. We attempted to create and verify a discriminant formula for use as a diagnostic aid for the early diagnosis of SBO. This retrospective study included 97 patients who underwent an operation for SBO from January 2007 to September 2018. First, a discriminant analysis was performed for 73 patients who underwent an operation from January 2007 to December 2015 in order to obtain a formula. Next, we analyzed 34 patients who underwent an operation from January 2016 to September 2018 to verify the formula. The risk factors for SBO included ascites, signs of preperitoneal irritation, and lactate > 1.16 mmol/L. The discriminant formula is as follows: 1.954 × collection of ascites (1 or 0) + 1.239 × peritoneal irritation sign (1 or 0) + 0.378 × lactate − 2.331 (1: positive, 0: negative). The predictive value was as follows: sensitivity, 87.5%; specificity, 64.7%; and predictive accuracy, 73.5%. In patients who presented within 24 h of the onset, the sensitivity was 92.3%, the specificity was 75.0%, and the predictive accuracy was 85.7%. Our discriminant formula seems useful for the rapid diagnosis of SBO.

Background In Japan, the multidisciplinary team approach in cancer chemotherapy has become quite widespread. However, patients treated with oral anticancer drugs in outpatient clinics usually receive short medical examinations from doctors without any intervention of pharmacists. To improve this medical circumstance, we made a skin disorder manual for community pharmacists and evaluated its feasibility. Methods Patients who underwent oral skin toxic chemotherapy from May 1, 2017, to October 31, 2017, were enrolled. The severity of skin toxicities was evaluated based on NCI-CTCAE ver4.0. Skin care and skin disorders were assessed by community pharmacists based on the assessment document arranged by the investigator. Numbers of patients who replied to the assessment, numbers of replies, numbers of assessments and instructions for skin care, and numbers of prescription proposals were evaluated to assess the value of intervention of community pharmacists. Results Sixty-two patients were enrolled in this study. Community pharmacy responded to 55 patients (88.7%), for a total of 335 replies. The data described in the replies were as follows: 317 assessments of skin disorders (94.6%), 307 assessments of skin care (91.6%), 248 instructions for skin care (74%), and 19 prescription proposals (5.7%). Conclusions Community pharmacists have high motivation for prevention and early detection of skin disorders. Although the number of prescription proposals is small, some proposals have contributed to improving side effects. Collaboration of hospital pharmacists and community pharmacists is important for prevention, early detection, and treatment of skin disorders caused by oral anticancer drugs.

The short-term results of single-incision laparoscopic colectomy (SILC) showed the safety, feasibility, and effectiveness when performed by skilled laparoscopic surgeons. However, the long-term complications, such as SILC-associated incisional hernia, have not been evaluated. The aim of this study was to determine the incidence of incisional hernia after SILC compared with multi-port laparoscopic colectomy (MPC) for colon cancer. From March 2012, to March 2015, a total of 200 patients were enrolled in this study. The patients were randomized to the MPC arm and SILC arm. A total of 200 patients (MPC arm; 100 patients, SILC arm; 100 patients) were therefore analyzed. In all cases the specimen was extracted through the umbilical port, which was extended according to the size of the specimen. A diagnosis of incisional hernia was made either based on a physical examination or computed tomography. The baseline factors were well balanced between the arms. The median follow-up period was 42.4 (range 9.4–70.0) months. Twenty-one patients were diagnosed with incisional hernia, giving an incidence rate of 12.1% in the MPC arm and 9.0% in the SILC arm at 36 months (P = 0.451). In the multivariate analysis, the body mass index (≥ 25 kg/m2) (hazard ratio [HR] 3.03; 95% confidence interval [CI] 1.03–8.92; P = 0.044), umbilical incision (≥ 5.0 cm) (HR 3.22; 95% CI 1.16–8.93; P = 0.025), and history of umbilical hernia (HR 3.16; 95% CI 1.02–9.77; P = 0.045) were shown to be correlated with incisional hernia. We found no significant difference in the incidence of incisional hernia after SILC arm versus MPC arm with a long-term follow-up. However, this result may be biased because all specimens were harvested through the umbilical port. The study was registered with the Japanese Clinical Trials Registry as UMIN000007220.

Introduction: This study examined the relationship between health literacy (HL), women’s health, and work productivity (i.e., absenteeism or presenteeism) among female workers in Japan. Methods: In February 2018, a web-based, nationwide survey was conducted among registered survey company monitors. The questionnaire included women’s HL, absenteeism, presenteeism, health behaviors for menstrual abnormalities and premenstrual syndrome (PMS), and demographic information. Overall, 2,596 monitors were randomly invited, and the survey included the first 2,000 respondents (average age = 35.8 years, SD = 8.1). An analysis of covariance (ANCOVA) was conducted to compare adjusted work productivity between two groups: the low-HL group and the high-HL group. The results were adjusted for age, education, employment status, number of children, and the presence of underlying gynecological diseases. Logistic regression analyses were performed to determine any differences in health behaviors for menstrual abnormalities or PMS between the two groups. The results were adjusted for age, education level, number of children, and employment status. Results: The ANCOVA showed that the high-HL group had significantly less presenteeism and better performance when experiencing PMS (p < 0.001 and p < 0.013, respectively) compared to the low-HL group after adjusting for covariates. However, the results showed no significant differences in absenteeism between the two groups. Logistic regression showed that the high-HL group had a significantly higher odds ratio (OR) than the low-HL group in terms of health behaviors for menstrual abnormalities or PMS (OR 2.82 and 1.86, respectively) after adjusting for covariates. Conclusions: Women’s HL may contribute to decreased presenteeism and better health behaviors regarding the use of medicine or medical services.

BackgroundBirth preparedness could be the key factor that influences the choice of birthplace with skilled birth attendants. To reduce the high maternal mortality of Tanzania, a large study was planned to develop a smartphone app to promote birth preparedness in a city area of Tanzania. This study aimed to identify factors that influence birth preparedness in the city area of Tanzania.MethodsPregnant women were asked to complete the Birth Preparedness Questionnaire during antenatal visits using tablets. Multiple linear regression analyses were performed to determine the sociodemographic and obstetric characteristics that influenced the factors.ResultsA total of 211 participants were included in the analysis. Distance from the nearest health facility negatively influenced the total score of the Birth Preparedness Assessment (β= 0.7,p = 0.02). Education higher than college positively influenced the total score (β = 4.76,p = 0.01). Decision-making of birthplace by other people (not women) negatively influencedFamily Support(β=1.18,p = 0.03). Having jobs negatively influencedPreparation of Money and Food(β=-1.02,p p = 0.03). Being single positively influencedPreparation of Money and Food(β = 0.35,p = 0.19) andPreference of Skilled Birth Attendants(β = 0.42,p = 0.04). Experience of losing a baby negatively influenced the knowledge (β=0.80,p Preference of Skilled Birth Attendants(β=0.38,p = 0.02).ConclusionsThe findings showed an updated information on pregnant Tanzanian women living in an urban area where rapid environmental development was observed. Birth preparedness was negatively affected when women reside far from the health facilities, the birthplace decision-making was taken by others beside the women, women have jobs, and when women have experienced the loss of a baby. We hope to use the information from this study as content in our future study, in which we will be applying a smartphone app intervention for healthy pregnancy and birth preparedness. This information will also help in guiding the analysis of this future study. Although generalization of the study needs careful consideration, it is important to reconsider issues surrounding birth preparedness as women’s roles both in the family and society, are more, especially in urban settings.

Recent pacemakers with transthoracic impedance sensors have a specific algorithm identifying sleep apnea (SA). Our aim was to evaluate the algorithm in Japanese patients.Consecutive patients implanted with a pacemaker with sleep apnea monitoring algorithm at our hospital were enrolled prospectively. After implantation, patients underwent polysomnography (PSG). The respiratory disturbance index measured by pacemaker (RDI-PM) was extracted in the morning after PSG.Forty-five patients were recruited; 78% of patients underwent overnight PSG completely, and among them RDI-PM was invalid for one patient. Then the analysis was performed in 34 patients. Moderate/severe SA (apnea hypopnea index, AHI≥15events/h) and severe SA (AHI≥30events/h) by PSG were diagnosed in 65% and 41% of patients. The mean AHI-PSG and RDI-PM were 30.4±22.6 and 21.7±14.2events/h, respectively. There was a significant positive correlation between AHI-PSG and RDI-PM (r=0.543; p=0.001). The correlation was stronger in the severe SA group (r=0.664; p=0.010), in a group whose apnea index was higher than hypopnea index (r=0.822; p=0.002), and in a group whose central sleep apnea (CSA) index was higher than obstructive sleep apnea index (r=0.977; p0.001). RDI-PM cut-off value for identifying severe SA was 22 (area under the curve, 0.682; sensitivity, 64%; specificity, 75%).The pacemaker-based algorithm is a useful screening tool for SA in Japanese individuals, especially in the severe SA group, apnea-dominant group, and CSA-dominant group.

OBJECTIVES The aim of this study was to predict increased alcohol and tobacco use in Fukushima nuclear power plant (NPP) workers 3 years after a nuclear disaster. METHODS Surveys were conducted in two postdisaster waves (Wave 1: 2 to 3 months; Wave 2: 32 months). Adjusted risk ratio (aRR) was computed to assess the covariates of increased alcohol and tobacco use in Wave 2. RESULTS Increased alcohol use was associated with age of 29 years or less [aRR (95% confidence interval (95% CI): 1.26 (1.01 to 1.57)], major property loss [1.25 (95% CI 1.02 to 1.55)], and high posttraumatic stress responses (PTSRs) [1.34 (95% CI 1.08 to 1.67)] in Wave 1. Increased tobacco use was associated with age of 29 years or less [1.46 (95% CI 1.12 to 1.90)] and high PTSR [1.62 (95% CI 1.25 to 2.10)] in Wave 1 (P

We examined the association between caregiver burden and work productivity (i.e., absenteeism, presenteeism, and overall work impairment) among working family caregivers of people with dementia and whether job characteristics (i.e., job demands, job control, supervisor and coworker support) moderate this association. A cross-sectional correlational study design using a web-based questionnaire survey was conducted among 379 Japanese working family caregivers of people with dementia (105 female, age range 20–77) in May 2016, which measured caregiver burden, work productivity, care situation, job characteristics, and demographics. Caregiver burden was designated as an independent variable and each aspect of work productivity as a dependent variable in a hierarchical multiple regression analysis, adjusting for demographics. Interaction terms between caregiver burden and each job characteristic were also included in the model. Caregiver burden was significantly and positively associated with presenteeism (β = 0.219, p

Following the 2018 rubella outbreak in Japan, this study aimed to assess rubella prevention measures based on the vaccination and immunization status of pregnant women in Japan. Our cohort study involved 3 local core hospitals in Yokohama City, and a total of 666 pregnant women were recruited between June 2018 and September 2019 and answered an online questionnaire. In total, 67.5% of the pregnant women had received rubella vaccination. The rate of rubella vaccination among pregnant women in the present survey was lower than that among age-matched female participants in a nationwide survey conducted in 2018. Overall, the study results showed that pregnant women in their 20s had a higher vaccination rate than those in their 40s, women who were nonsmokers before pregnancy had a higher vaccination rate than those who were smokers, and pregnant women who were aware that rubella may affect their fetuses had a higher vaccination rate than those who were unaware of this. This survey elucidated multiple predictive factors for rubella vaccination among pregnant women in Japan. Our results confirm the recommendation that women considering pregnancy should be vaccinated against rubella.

Postoperative delirium (POD) and subsyndromal delirium (SSD) among older patients is a common, serious condition associated with a high incidence of negative outcomes. However, there are few accurate methods for the early detection of POD and SSD in surgical wards. This study aimed to identify risk factors of POD and SSD in older patients who were scheduled for surgery in a surgical ward. This was a prospective observational study. Study participants were older than 65 years, underwent urology surgery, and were hospitalized in the surgical ward between April and September 2019. Delirium symptoms were assessed using the Confusion Assessment Method (CAM) on the preoperative day, the day of surgery, and postoperative days 1–3 by the surgical ward nurses. SSD was defined as the presence of one or more CAM criteria and the absence of a diagnosis of delirium based on the CAM algorithm. Personal characteristics, clinical data, cognitive function, physical functions, laboratory test results, medication use, type of surgery and anesthesia, and use of physical restraint and bed sensor were collected from medical records. Multiple logistic regression analyses were conducted to identify the risk factors for both POD and SSD. A total of 101 participants (mean age 74.9 years) were enrolled; 19 (18.8%) developed POD (n = 4) and SSD (n = 15). The use of bed sensors (odds ratio 10.2, p = .001) was identified as a risk factor for both POD and SSD. Our findings suggest that the use of bed sensors might be related to the development of both POD and SSD among older patients in surgical wards.

Background Nivolumab, the anti-programmed cell death protein 1 antibody, has been approved for advanced melanoma, mainly based on evidence from Western countries. The profile of melanoma differs between Caucasian and Asian patients. This study was performed to obtain post-marketing data of nivolumab in Japanese patients with advanced melanoma. Methods This prospective, observational study involved patients with unresectable or metastatic melanoma treated with nivolumab at dosages of 2 mg/kg every 3 weeks or 3 mg/kg every 2 weeks. The primary endpoints were objective response rate and overall survival. The secondary endpoints were progression-free survival and the objective response rate according to immune-related Response Evaluation Criteria in Solid Tumours. Result Among 124 patients analysed, mucosal melanoma was the most common subtype, followed by acral lentiginous, nodular, superficial spreading and lentigo maligna melanoma. Response Evaluation Criteria in Solid Tumours evaluation showed an objective response rate of 17.7%. The median survival time was 15.93 months, and the 1-year overall survival rate was 66%. Outcomes were not significantly different among melanoma subtypes. Better overall survival and/or progression-free survival but not objective response rate were associated with performance status 0, lower levels of lactate dehydrogenase, C-reactive protein and neutrophil-to-lymphocyte ratio. Patients with immune-related adverse events showed a better objective response rate, 3-month landmark overall survival and progression-free survival than patients without immune-related adverse events. Conclusion The objective response rate and median survival time in Japanese patients treated with nivolumab were lower in daily practice than the >30% and >30 months, respectively, seen in global phase III trials. The occurrence of immune-related adverse events may be a predictor for survival and response to treatment with nivolumab., Efficacy of nivolumab was lower in post-marketing surveillance of Japanese patients with melanoma than in global trials. Immune-related adverse events were suggested to be efficacy predictors by 3-month landmark analysis.

The aim of the present study was to investigate the psychological effects of the COVID-19 outbreak and associated factors on hospital workers at the beginning of the outbreak with a large disease cluster on the Diamond Princess cruise ship. This cross-sectional, survey-based study collected demographic data, mental health measurements, and stress-related questionnaires from workers in 2 hospitals in Yokohama, Japan, from March 23, 2020, to April 6, 2020. The prevalence rates of general psychological distress and event-related distress were assessed using the 12-item General Health Questionnaire (GHQ-12) and the 22-item Impact of Event Scale-Revised (IES-R), respectively. Exploratory factor analysis was conducted on the 26-item stress-related questionnaires. Multivariable logistic regression analysis was performed to identify factors associated with mental health outcomes for workers both at high- and low-risk for infection of COVID-19. A questionnaire was distributed to 4133 hospital workers, and 2697 (65.3%) valid questionnaires were used for analyses. Overall, 536 (20.0%) were high-risk workers, 944 (35.0%) of all hospital workers showed general distress, and 189 (7.0%) demonstrated event-related distress. Multivariable logistic regression analyses revealed that ‘Feeling of being isolated and discriminated’ was associated with both the general and event-related distress for both the high- and low-risk workers. In this survey, not only high-risk workers but also low-risk workers in the hospitals admitting COVID-19 patients reported experiencing psychological distress at the beginning of the outbreak.

Aim The present study clarified the effect on the health‐related quality of life and patient satisfaction of single‐incision laparoscopic colectomy compared with multiport laparoscopic colectomy for colorectal cancer. Methods We conducted a multicenter, randomized, control trial comparing single‐incision and multiport laparoscopic colectomy for colon cancer. We performed a pre‐planned secondary analysis of health‐related quality of life and patient satisfaction data of 200 patients. Health‐related quality of life was evaluated using the Japanese 36‐item Short Form Health Survey (SF‐36) version 2.0 before surgery and at 1 month after surgery. Patient satisfaction was compared using seven questionnaires at 1 month after surgery. Results One hundred patients were assigned to each group. After excluding 18 patients (9.0%) who did not complete the SF‐36, 182 patients (91.0%) were included in the analysis (92 cases of single‐incision laparoscopic colectomy and 90 cases of multiport laparoscopic colectomy). The SF‐36 scores at 1 month after surgery were not significantly different between the two arms. The role physical, bodily pain, vitality and physical component summary were significantly lower at 1 month after surgery than before in both groups. However, the role emotional was significantly lower after surgery than before only in the single‐incision laparoscopic colectomy group. In terms of patient satisfaction at 1 month after surgery, there were no significant differences in any of the seven items on the questionnaire. Conclusions Single‐incision laparoscopic colectomy was similar to multiport laparoscopic colectomy in terms of health‐related quality of life and patient satisfaction. However, single‐incision laparoscopic colectomy may be inferior than multiport laparoscopic colectomy in terms of the role emotional., We demonstrated in this sub‐analysis of a multicenter, randomized controlled trial comparing single‐incision laparoscopic colectomy (SILC) and multiport laparoscopic colectomy (MPLC) for colon cancer patients that SILC was similar to MPLC in terms of health‐related quality of life and satisfaction. However, SILC may be inferior in terms of the role emotional.

Summary Background The laxative drug lubiprostone improves intestinal permeability in healthy volunteers. We aimed to assess efficacy and safety of lubiprostone in patients with non-alcoholic fatty liver disease (NAFLD) with constipation via attenuation of intestinal permeability. Methods This randomised, double-blind, placebo-controlled, phase 2a study in Yokohama City University Hospital, Japan, recruited patients (aged 20–85 years) with NAFLD and constipation, alanine aminotransferase (ALT) at least 40 U/L, liver stiffness (≤6·7 kPa), and hepatic fat fraction at least 5·2% when assessed by MRI-proton density fat fraction. Eligible patients were randomly assigned (11:10:9) by a computer-based system and stratified by age and sex to receive 24 μg lubiprostone, 12 μg lubiprostone, or placebo, orally, once per day for 12 weeks. The primary endpoint was the absolute changes in ALT at 12 weeks. Efficacy analysis was done by intention to treat. Safety was assessed in all treated patients. This trial was registered with University Hospital Medical Information Network Clinical Trials Registry (UMIN000026635). Findings Between March 24, 2017, and April 3, 2018, we screened 288 patients, of whom 150 (52%) were randomly assigned to treatment: 55 patients were assigned to receive 24 μg lubiprostone, 50 to receive 12 μg lubiprostone, and 45 to receive placebo. A greater decrease in the absolute ALT levels from baseline to 12 weeks was seen in the 24 μg lubiprostone group (mean −13 U/L [SD 19]) than in the placebo group (1 U/L [24]; mean difference −15 U/L [95% CI −23 to −6], p=0·0007) and in the 12 μg lubiprostone group (−12 U/L [21]) than in the placebo group (mean difference −13 U/L [–22 to −5], p=0·0023). 18 (33%) of 55 patients in the 24 μg group had at least one adverse event, as did three (6%) of 47 patients in the 12 μg group and three (7%) of 43 in the placebo group. The most common adverse event was diarrhoea (17 [31%] of patients in the 24 μg group, three [6%] in the 12 μg group, none in the placebo group). No life-threatening events or treatment-related deaths occurred. Interpretation Lubiprostone was well tolerated and reduced the levels of liver enzymes in patients with NAFLD and constipation. Further studies are necessary to better define the efficacy and tolerability of lubiprostone in patients with NAFLD without constipation. Funding Mylan EPD G.K.

Background: The laxative drug lubiprostone (LUB) was previously shown to improve intestinal permeability in healthy volunteers. We aimed to evaluate the efficacy and safety of LUB in patients with non-alcoholic fatty liver disease (NAFLD) via attenuation of intestinal permeability. Methods: In this randomized, double-blind, placebo-controlled, phase 2a study, NAFLD patients were randomly assigned to receive oral LUB doses (24 μg or 12 μg, once a day) or placebo for 12 weeks. All participants and investigators were blinded to the treatment groups. The primary and key secondary endpoints were the absolute changes in alanine aminotransferase (ALT) levels and lactulose-mannitol ratio (LMR), which was indicator for intestinal permeability, after 12 weeks. LMR responders and non-responders were defined as LMR 0. Findings: In total, 150 patients were randomly assigned to receive 24 μg of LUB (LUB24, n=55), 12 μg of LUB (LUB12, n=50), or placebo (n=45). We observed a significant decrease in absolute ALT levels in the LUB24 (−13 vs. 1 IU/L, p=0·0007) and LUB12 groups (−12 vs. −1 IU/L, p=0·002) compared to those in the placebo group. Compared to the non-responders, the LMR responders showed a significant reduction in absolute ALT levels in the LUB24 (−21 vs. 2 IU/L, p=0·002) and LUB12 groups (−21 vs. 6 IU/L, p=0·0007). Adverse events were more frequently reported in the LUB24 group than in the LUB12 and placebo groups. Interpretation: LUB was well tolerated and significantly reduced the levels of liver enzymes as well as intestinal permeability in NAFLD patients. The greater reduction in LMR responders suggested that manipulation of intestinal permeability may be a promising novel treatment approach for NAFLD. Nevertheless, further studies are necessary to better define the efficacy and tolerability of LUB in NAFLD patients. Trial Registration: This trial is registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000026635). Funding Statement: This investigator-initiated clinical trial was conducted by the Yokohama City University - as the sponsor - and funded by Mylan EPD G.K. Declaration of Interests: AN reports grant and research support from Gilead, Mylan EPD, EA Pharma, Kowa, Taisho, and Biofermine and is a consulting adviser for Gilead, Boehringer Ingelheim, BMS, Kowa, Asteras, EA Pharma, and Mylan EPD. Other authors declare no competing interests. Ethics Approval Statement: The study protocol complied with both the Declaration of Helsinki and the Ethics Guidelines for Clinical Research published by the Ministry of Health, Labour and Welfare of Japan. The study protocol and relevant supporting data were approved by local ethics committees on November 21, 2016, prior to the initiation of the study.

BACKGROUND This paper reports the protocol of a randomised, double-blind, placebo-controlled study to test the efficacy, safety, and tolerability of lubiprostone (LUB) vs. placebo on suppressing gut permeability in non-alcoholic fatty liver disease (NAFLD) patients with constipation. NAFLD, including non-alcoholic steatohepatitis (NASH), is a common chronic liver disorder. Progression is associated with increased gut permeability and gut-derived endotoxins. Most NAFLD/NASH clinical trial drugs aim to improve liver function or systemic metabolism. LUB is a type 2 chloride channel activator used as a laxative for the treatment of patients with constipation. LUB suppresses gut permeability induced by non-steroidal anti-inflammatory drugs in healthy volunteers and lowers blood endotoxin levels. There have been no clinical studies of LUB for NAFLD/NASH patients. METHODS The study plans to enrol adult patients (20-85 years, planned enrolment, n = 150; planned sample size, n = 120) with NAFLD and constipation, alanine aminotransferase ≥40 IU/L, equivalent steatosis grade ≥1, and equivalent fibrosis stage

Diabetes mellitus (DM) is a major risk factor for the development of coronary artery disease (CAD) ([1][1]) and coronary microvascular dysfunction is a key feature of diabetic heart disease ([2][2]). An assessment of the microvascular function is important for patients with DM because diffuse

Background In Tanzania, the information on Birth Preparedness and Complication Readiness is insufficiently provided to pregnant women and their families. The aim of this study was to evaluate the maternal and infant outcomes of a family-oriented antenatal group education program that promotes Birth Preparedness and Complication Readiness in rural Tanzania. Methods Pregnant women and families were enrolled in a program about nutrition and exercise, danger signs, and birth preparedness. The cross sectional survey was conducted one year later to evaluate if the participants of the program (intervention group) were different from those who did not participate (control group) with respect to birth-preparedness and maternal and infant outcomes. Results A total of 194 participants (intervention group, 50; control group, 144) were analyzed. For Birth Preparedness and Complication Readiness, the intervention group participants knew a health facility in case of emergency (OR: 3.11, 95% CI: 1.39–6.97); arranged accompaniment to go to a health facility for birth (OR: 2.56, 95% CI: 1.17–5.60); decided the birthplace with or by the pregnant women (OR: 3.11, 95% CI: 1.44–6.70); and attended antenatal clinic more than four times (OR: 2.39, 95% CI: 1.20–4.78). For birth outcomes, the intervention group had less bleeding or seizure during labour and birth (OR: 0.28, 95%CI: 0.13–0.58); fewer Caesarean sections (OR: 0.16, 95% CI: 0.07–0.36); and less neonatal complications (OR: 0.28, 95% CI: 0.13–0.60). Conclusions The four variables were significantly better in the intervention group, i.e., identifying a health facility for emergencies, family accompaniment for facility birth, antenatal visits, and involvement of women in decision-making, which may be key factors for improving birth outcome variables. Having identified these key factors, male involvement and healthy pregnant lives should be emphasized in antenatal education to reduce pregnancy and childbirth complications. Trial registration No.2013–273-NA-2013-101. Registered 12 August 2013.

The authors have noted that the number of participants in the final sample should be 377, rather than 379. In this correction, the two mistaken cases were removed and analyses were repeated with 377 cases.

Objective To examine the necessity and sufficiency of different types of hysterectomy for the surgical treatment of endometrial cancer. Methods This was a multicenter collaborative study conducted by 11 institutions. Among patients with stage I–III endometrial cancer who underwent surgery as the initial treatment (only chemotherapy was provided if adjuvant therapy was needed) from 2001 to 2012, we retrospectively examined the type of hysterectomy, clinicopathological factors, recurrence rate over a maximum period of 5 years, and the site of recurrence. The local recurrence rate was examined by univariate and multivariate analyses. Results Among 1335 patients, 982 (73.6%) underwent simple hysterectomy (SH) and 353 (26.4%) underwent modified radical hysterectomy (mRH) and were observed for a mean duration of 51.8 months. No significant difference was observed in the rate of local recurrence between the SH and mRH groups (p = 0.928). In multivariate analysis, clinicopathological factors independently associated with localized recurrence included postmenopausal status [hazard ratio (HR) 5.036, 95% confidence interval (CI) 1.506–16.841, p = 0.009], with stages II (HR 3.337, 95% CI 1.701–6.547, p

Background: Chemotherapy often results in dermatologic toxicities, which decrease quality of life (QOL) of cancer patients. These adverse skin reactions sometimes happen simultaneously. Though previous reports have demonstrated that skin reactions influence QOL, those reports were focused on only one kind of skin toxicity or on the most serious skin toxicity. The aim of this study is to demonstrate the contribution of each skin toxicity to QOL. Methods: This is a cross-sectional study at Kinki Central Hospital. Patients were enrolled who underwent skin toxic chemotherapy from April 1 to June 30, 2017. DLQI and Skindex29 were used to grade the QOL of patients. Also, the severity of skin toxicities was evaluated based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE ver4.0). We investigated how QOL changed with patient demographic and clinical characteristics, the worst skin toxicity grade, and each skin toxicity using statistical analyses. Results: No significant differences were detected between QOL scores (total score of DLQI, emotions domain, symptoms domain, functioning domain and total score of Skindex29) and patient demographic and clinical characteristics (P values were 0.155, 0.086, 0.052, 0.312 and 0.114, respectively). There were statistically significant QOL differences among the grades of the worst skin toxicity (P values were

AIM The human papillomavirus (HPV) vaccination rate in Japan fell to nearly 0% following widespread coverage of possible adverse events. Developing a next approach to promote the effective prevention of HPV-related diseases including cervical cancer (CC) in Japan requires comprehensive understanding of knowledge and attitudes regarding CC prevention, HPV infection and HPV vaccination among the population including laypersons and medical professions in Japan. METHODS A questionnaire survey was administered in a wide variety of settings in Japan. The questionnaire contained items on knowledge about CC, HPV infection and HPV vaccination; awareness of the HPV vaccine's effectiveness and associated adverse events; and attitudes toward the HPV vaccination for their daughters and for men/boys. RESULTS Of 3033 targeted people, complete survey responses were received from 1182 men and 1602 women (total: 2784). The male laypersons' group had significantly lower knowledge than did the female laypersons' group (adjusted odds ratio, aOR = 3.86, P

Background Anti-PD-1 antibody nivolumab has been approved for advanced melanoma in Japan. Although there have been clinical trial reports on nivolumab treatment for advanced melanoma, real-world data on the efficacy of nivolumab in an Asian patient cohort is still lacking. The aim of this study is to obtain real-world data on the efficacy of nivolumab in Japanese patients with advanced melanoma. Methods This prospective observational study was performed on unresectable or metastatic melanoma patients who were treated with nivolumab. Primary endpoints were response rate (RR), and overall survival (OS). The secondary endpoints were progression-free survival (PFS) and the immune-related adverse events (irAEs) ratio. Results In total, 124 patients from 22 institutions in Japan were enrolled between Dec. 2015 and Dec. 2017. Mucosal melanoma (34%) was the most frequent subtype in this study, followed by acral lentiginous melanoma (20%), nodular melanoma (15%), superficial spreading melanoma (13%). We observed complete response (CR) in 2 (2%), partial response (PR) in 21 (17%), stable disease (SD) in 27 (22%), and progressive disease (PD) in 59 patients (47.6%) (objective RR: 19%). Use of nivolumab as first-line treatment showed a tendency toward higher response than when used as second-line treatment (objective RR, 23% vs 11%, P = 0.12). IrAEs comprised skin reactions and endocrine-related adverse effects. The median PFS in patients with skin reactions (or skin-related irAEs) was 8.61 months compared to 2.14 months without skin-related irAEs, and 8.99 months (p Conclusions The results of this interim analysis showed a lower RR than that reported in recent phase 2 trials conducted in Japan. The differences in the proportions of melanoma subtypes, with a higher proportion of mucosal and acral melanoma, and use of nivolumab as second-line treatment will probably lead to a lower RR to nivolumab in Japan. As the results of this study showed that the occurrence of irAEs had a significant impact on therapeutic efficiency, it is critical to take appropriate measures to manage the occurrence of irAEs. Legal entity responsible for the study The authors. Funding This study was sponsored by Public Health Research Foundation under the funding support from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb K.K. Disclosure N. Yamazaki: Honoraria (self), Honoraria (institution), Non-remunerated activity/ies: ONO Phamaceuticals; Honoraria (self), Honoraria (institution), Non-remunerated activity/ies: Bristol-Myers Squibb; Honoraria (self), Honoraria (institution), Non-remunerated activity/ies: Novartis Pharma K.K.; Honoraria (self), Honoraria (institution), Non-remunerated activity/ies: MSD K.K.; Honoraria (self), Honoraria (institution): Merck Serono Co., Ltd.; Honoraria (self): Takeda Pharmaceutical Co., Ltd. K. Namikawa: Honoraria (institution): Public Health Research Foundation; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp & Dohme. T. Takenouchi: Advisory / Consultancy: Ono Pharmaceutical Co., Ltd.; Advisory / Consultancy: MSD KK; Advisory / Consultancy: Chugai Pharmaceutical Co., LTD.; Advisory / Consultancy: Novartis Pharma KK. Y. Nakamura: Honoraria (self): ONO pharmaceuticals; Honoraria (self): MSD; Honoraria (self): Bristol Myers-Squibb; Honoraria (self): Novartis Pharma K.K.; Honoraria (self): Taisho Toyama Pharma; Honoraria (self): Maruho; Honoraria (self): Taiho Pharma. S. Kitano: Honoraria (self): AstraZeneca; Honoraria (self): Chugai; Honoraria (self): Pfizer; Honoraria (self): Sanofi; Honoraria (self): Nippon Kayaku; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Meiji Seika Pharma; Honoraria (self): Taiho. T. Fujita: Honoraria (self): Public Health Research Foundation; Advisory / Consultancy: ONO PHARMACEUTICAL CO., LTD; Advisory / Consultancy: Bristol-Myers Squibb Company. T. Yamanaka: Honoraria (self), Honoraria (institution): Takeda; Honoraria (self), Honoraria (institution): Taiho; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Chugai. Y. Kawakami: Advisory / Consultancy: Public Health Research Foundation; Advisory / Consultancy: Ono Pharmaceutical Co., LTD; Advisory / Consultancy: Bristol-Myers Squibb Company. All other authors have declared no conflicts of interest.

We previously reported that aberrant expression of atypical protein kinase C λ/ι (aPKCλ/ι) in low-grade squamous intraepithelial uterine cervix lesions was associated with an increased risk of progression to higher grade. This study aimed to investigate aPKCλ/ι expression patterns in cervical squamous cell carcinoma (SCC) and its association with disease progression. We immunohistochemically assessed aPKCλ/ι expression in 168 SCC samples and 13 normal uterine cervix samples. In 69.0% of SCC cases, aPKCλ/ι was expressed more abundantly than in normal epithelium, but there was no significant association between aPKCλ/ι intensity and disease progression (P=0.087, Cochran-Mantel-Haenszel test). aPKCλ/ι in normal cervical epithelium was confined to the cytoplasm or intercellular junctions. In contrast, aPKCλ/ι was predominantly localized within the nucleus in 36.9% of SCC samples (P

Background To increase births attended by skilled birth attendants in Tanzania, studies have identified the need for involvement of the whole family in pregnancy and childbirth education. This study aimed to develop, implement, and evaluate a family-oriented antenatal group educational program to promote healthy pregnancy and family involvement in rural Tanzania. Methods This was a quasi-experimental 1 group pre-test/post-test study with antenatal education provided to pregnant women and their families in rural Tanzania. Before and after the educational program, the pre-test/post-test study was conducted using a 34-item Birth Preparedness Questionnaire. Acceptability of the educational program was qualitatively assessed. Results One-hundred and thirty-eight participants (42 pregnant women, 96 family members) attended the educational program, answered the questionnaire, and participated in the feasibility inquiry. The mean knowledge scores significantly increased between the pre-test and the post-test, 7.92 and 8.33, respectively (p = 0.001). For both pregnant women and family members, the educational program improved Family Support (p = 0.001 and p = 0.000) and Preparation of Money and Food (p = 0.000 and p = 0.000). For family members, the scores for Birth Preparedness (p = 0.006) and Avoidance of Medical Intervention (reversed item) (p = 0.002) significantly increased. Despite the educational program, the score for Home-based Value (reversed item) (p = 0.022) and References of SBA (p = 0.049) decreased in pregnant women. Through group discussions, favorable comments about the program and materials were received. The comments of the husbands reflected their better understanding and appreciation of their role in supporting their wives during the antenatal period. Conclusions The family-oriented antenatal group educational program has potential to increase knowledge, birth preparedness, and awareness of the need for family support among pregnant women and their families in rural Tanzania. As the contents of the program can be taught easily by reading the picture drama, lay personnel, such as community health workers or traditional birth attendants, can use it in villages. Further development of the Birth Preparedness Questionnaire is necessary to strengthen the involved factors. A larger scale study with a more robust Birth Preparedness Questionnaire and documentation of skilled care use is needed for the next step. Trial registration No.2013–273-NA-2013-101. Registered 12 August 2013.

Psychological detachment from work, an off-job experience of "switching off" mentally, seems to be crucial for promoting employee's well-being. Previous studies on predictors of psychological detachment mainly focused on job-related factors, and only a few studies focused on family-related and personal factors. This study focuses not only on job-related factors (job demands, job control, workplace support) but also on family-related (family/friend support) and personal factors (workaholism), and examines the relation of these three factors with psychological detachment. Data of 2,520 Japanese employees was randomly split into two groups and then analyzed using cross-validation. Hierarchical multiple regression analyses revealed that family/friend support had a positive association with psychological detachment, whereas a subscale of workaholism (i.e. working compulsively) had negative associations with it across the two groups. Results suggest that family/friend support would facilitate psychological detachment whereas workaholism would inhibit it. Refereed/Peer-reviewed

A newly designed removable appliance with a shape-memory wire was used for the orthodontic treatment of the anterior teeth in an 11-year-old child who had autism and intellectual disability. The device was designed to reduce the lateral incisor crossbite and the central incisors' labial rotation. The child was treated for 1 year with this removable appliance. Tooth movement was analyzed using cephalograms and surface data were derived from study models. This device proved to be very durable. The lateral incisor crossbite was corrected, and the inclination of the upper central incisors and the interincisal angle were improved. This appliance exerts light and continuous orthodontic force, without requiring any adjustments of the spring wire. The appliance also facilitated orthodontic treatment in a child with intellectual disability in whom treatment with a standard orthodontic device would be unsuitable.

Pegylated interferon and ribavirin combination therapy is the standard treatment for patients with chronic hepatitis C (CHC), but treatment failure can be difficult to predict. We and others have reported a relation between lipid values and sustained viral responses in patients with CHC. However, the relationship between lipid values and treatment failure has not been previously reported. The present study investigated the association between the profiles of phospholipids and free cholesterol (FC), the main constitutive ingredients of the surface of lipoprotein, classified according to particle size and hepatitis C treatment, and determined the usefulness of these parameters for predicting the outcome of treatment. Fifty-five patients with CHC (33 men and 22 women) were included in the study. The serum total cholesterol, triglyceride, phospholipids, and FC levels in the lipoprotein subclasses were determined using high-performance liquid chromatography with gel permeation columns, enabling the lipoproteins to be classified into 13 subclasses according to particle size. According to a univariate analysis, the treatment failure group had a significantly higher serum phospholipid level overall in the high-density lipoprotein (HDL) and medium HDL fractions as well as a higher serum FC level in the HDL fraction and all HDL subclass fractions compared with the corresponding values in the non-nonvirological response group. Higher serum phospholipid and FC concentrations in the HDL subclasses were predictive of a failure to respond in patients with genotype 1b.

A 65-year-old man was admitted with penile tenderness and dysuria due to priapism. Enhanced computed tomography revealed metastatic tumors in the liver, lung, sacrum and lymph nodes. Advanced rectal cancer, detected by colonoscopy as a primary tumor, was treated with chemotherapy (FOLFOX4). Although the rectal cancer showed no change, five months of chemotherapy improveid the priapism, suggesting that chemotherapy can improve rare symptoms of rectal cancer.

Purpose To determine the prevalence and progression of Barrett’s epithelium and associated risk factors in Japan. Methods The study population comprised 869 cases. Endoscopic Barrett’s epithelium was diagnosed based on the Prague C & M Criteria. The correlations of clinical factors with the prevalence and progression of endoscopic Barrett’s epithelium were examined. Results Endoscopic Barrett’s epithelium was diagnosed in 374 cases (43%), in the majority of which the diagnosis was short-segment Barrett’s esophagus. The progression of Barrett’s epithelium was identified in 47 cases. In univariate and multiple logistic regression analyses, aging, smoking habit, and erosive esophagitis were significantly associated with the prevalence of Barrett’s epithelium, whereas aging and erosive esophagitis, especially severe erosive esophagitis, were significant contributing factors to the progression of Barrett’s epithelium. Conclusions Forty-three percent of the total study population was diagnosed as having endoscopic Barrett’s epithelium. During the follow-up period, 12.6% of the cases with Barrett’s epithelium exhibited progression which was associated with aging and severe erosive esophagitis.

The endoscopic examination of a 64-year-old male patient revealed a gastric submucosal tumor in the anterior wall of the gastric antrum. The lesion increased in diameter to 25 mm and was resected completely with endoscopic submucosal dissection (ESD). Histological examination of the submucosal tumor gave a diagnosis of an inflammatory fibroid polyp (IFP). It is suggested that ESD may be an effective and safe therapy for gastric submucosal tumors.

Objectives The Great East Japan Earthquake caused severe infrastructure damage in the Kanto and Tohoku regions, but the psychological stress of public sector employees in the Kanto region where tsunami damage was small has received little attention. This study examined the association between personal resilience and post-traumatic stress symptoms of local government employees in the Kanto region. Methods In this cross-sectional study, all employees (N=2,069) of a single municipality in the Kanto region were recruited in September 2011, six months after the earthquake, and 991 completed the questionnaire (response rate, 47.9%). After excluding respondents who had missing values, the data from 825 respondents (607 males and 218 females) were analyzed. Post-traumatic stress symptoms were measured using the Impact Event Scale-Revised. Resilience was measured using the Connor-Davidson Resilience Scale and divided into three groups on the basis of scores; low, moderate, and high. House damage and respondents or their families' experience of injury that were caused by the earthquake were assessed using single-item questions. Participants who reported house damage or injury were defined as being affected. Using multiple logistic regression analysis, the odds ratio of post-traumatic stress symptoms (IES-R score ≥25) was calculated for the upper, middle, and low resilience score groups. Results Among the respondents, 4.6% experienced injuries within their families, 82.3% reported house damage, and thus 83.3% were affected by the Great East Japan Earthquake. Post-traumatic stress symptoms were significantly higher among the affected group and those with chronic diseases. After adjusting for the demographic and occupational characteristics, the likelihood of post-traumatic stress symptoms was greater in the low resilience group (Odds ratio: 2.10 [95% confidence interval = 1.31-3.37]). A significant negative relationship was observed between resilience and post-traumatic stress symptoms particularly in the affected group. Conclusions Low personal resilience predicted post-traumatic stress symptoms among local government employees who experienced some house damage or injury during the Great East Japan Earthquake. This result may indicate that resilience reduces the onset of post-traumatic stress symptoms, even when faced by the difficulties imposed by a natural disaster such as an earthquake.