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Treating neuropathic pain is challenging and novel non-opioid-based medicines are needed. Using unbiased receptomics, transcriptomic analyses, immunofluorescence, and in situ hybridization, we found that the expression of the orphan GPCR Gpr160 and GPR160 increased in the rodent dorsal horn of the spinal cord following traumatic nerve injury. Genetic and immunopharmacological approaches demonstrated that GPR160 inhibition in the spinal cord prevented and reversed neuropathic pain in male and female rodents without altering normal pain response. GPR160 inhibition in the spinal cord attenuated sensory processing in the thalamus, a key relay in the sensory discriminative pathways of pain. We also identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a GPR160 ligand. Inhibiting endogenous CARTp signaling in spinal cord attenuated neuropathic pain, whereas exogenous intrathecal CARTp evoked painful hypersensitivity through GPR160-dependent ERK and cAMP response element-binding protein (CREB). Our findings de-orphanize GPR160, identify it as a determinant of neuropathic pain and potential therapeutic target, and provide insights into its signaling pathways. CARTp is involved in many diseases including depression and reward and addiction; de-orphanization of GPR160 is a major step forward understanding the role of CARTp signaling in health and disease.

Study question From when do abnormality in gut microbiome and phenotypes of PCOS appear during the process of growth? Summary answer Reproductive phenotypes of PCOS appear from 6 weeks and metabolic phenotypes from 12 weeks onward. Alteration in gut microbiome appears as early as 4 weeks. What is known already The etiology of PCOS remains largely unknown, however PCOS is considered as a complex multigenic disorder with strong epigenetic and environmental influence. Previous studies have suggested that fetal over-exposure to androgens could be the main factor of the development of PCOS after birth. On the other hands, recent studies on both human and PCOS rodent models have demonstrated the association between PCOS and alteration of gut microbiome in adulthood. Furthermore, it was recently reported that gut microbiome in obese adolescent with PCOS is different from obese adolescent without PCOS. Study design, size, duration A rodent PCOS model induced by prenatal dehydroepiandrosterone (DHT) exposure was applied to this study. Phenotypes and gut microbiome were compared between PCOS model mice (n = 12/group) and control mice (n = 10/group) at each stage of growth; 4 weeks (prepuberty), 6 weeks (puberty), 8 weeks (adolescent), 12 weeks (young adult), and 16 weeks (adult). The determinants for PCOS phenotypes are onset of puberty, estrous cycle, morphology of ovaries, serum testosterone level, body weight, and insulin resistance. Participants/materials, setting, methods Pregnant dams were subcutaneously injected on days of 16, 17, and 18 of gestation with either sesame oil for control groups or sesame oil containing 250µg of DHT for prenatal DHT groups. The evaluation of PCOS phenotypes and gut microbiome in female offspring were performed at each stage of growth. For examination of gut microbiota, next generation sequencing and bioinformatics analysis of 16S rRNA genes were performed on DNA extracted from mouse fecal samples. Main results and the role of chance Prenatal DHT mice exhibited delayed puberty onset, disrupted estrous cycle, and significantly increased testosterone levels from 6 weeks onward. Significantly increased atretic antral follicles were observed in prenatal DHT mice at 6, 12, and 16 weeks. Prenatal DHT mice showed significantly decreased body weight at 4, 6, 8 weeks and increased body weight from 12 weeks onward. As for gut microbiome, alpha-diversity was significantly different between control and prenatal DHT mice from 8 weeks onward and beta-diversity was significantly different at 6 and 8 weeks. Altered composition of gut microbiota was observed as early as 4 weeks. At phylum level, Firmicutes are significantly increased in prenatal DHT mice at 4 and 8 weeks and decreased at 16 weeks. Actinobacteria phylum showed significant decrease at 6 and 8 weeks in prenatal DHT mice. At genus level, relative abundance of several bacterial taxa significantly differed between control and prenatal DHT mice; some taxa, such as Allobaculum, Adlercreutzia, Bilophila, Clostridium, Gemella, Gemmiger, Roseburia, Ruminococcus, Staphylococcus, and Sutterella, exhibited constant increase or decrease in prenatal DHT mice during the process of growth. Interestingly, Roseburia was never detected in prenatal DHT mice, while approximately half of control mice harbored Roseburia at 12 and 16 weeks. Limitations, reasons for caution It is not clearly determined whether alteration in gut microbiome is cause or result of PCOS development, although the changes in gut microbiome seemed to precede the appearance of typical PCOS phenotypes in the present study. Mouse model does not completely recapitulate human PCOS. Wider implications of the findings: Our findings suggest that prenatal androgen exposure causes alteration of gut microbiome from pre-puberty onward, even before PCOS phenotypes become apparent. Intervention for girls at risk of PCOS with pre/pro-biotics may prevent them from developing PCOS in future. Trial registration number Not applicable

Background Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit‐to‐visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐RHYTHM Registry was performed. Methods and Results Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 (age, 69.7±9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6±5.0 times) during the 2‐year follow‐up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP‐SD (P =0.015 for thromboembolism; HR, 2.60, 95% CI, 1.36–4.97, P =0.004 for major hemorrhage; and HR, 1.85, 95% CI, 1.11–3.07, P =0.018 for all‐cause death) after adjusting for components of the CHA 2 DS 2 ‐VASc score, warfarin and antiplatelet use, atrial fibrillation type, BP measurement times, and others. These findings were consistent when BP‐coefficient of variation was used instead of BP‐SD. Conclusions Systolic BP visit‐to‐visit variability was significantly associated with all adverse events in patients with nonvalvular atrial fibrillation. Further studies are needed to clarify the causality between BP variability and adverse outcomes in patients with nonvalvular atrial fibrillation. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique Identifier: UMIN000001569.

Introduction Heterozygous familial hypercholesterolemia (HeFH) exhibits substantially atherogenic substrate which involves coronary and peripheral arteries. Whether atherosclerosis in HeFH propagates to intracranial arteries causing stroke remains to be determined. Purpose To characterize intracranial artery stenosis (IAS) in subjects with HeFH. Methods 148 HeFH subjects who underwent MRI/MRA imaging to evaluate intracranial arteries were analyzed. IAS was defined as the presence of stenosis with its % diameter stenosis ≥25%. Clinical demographics and cardiovascular events (all-cause death, ACS, stroke and PAD) were compared in those with and without IAS. Results IAS was observed in 24.3% (=36/148) of study subjects. It was more frequently located at middle cerebral artery (30.6%=11/36), followed by internal carotid artery (25.0%=9/36). 47.2% of IAS exhibited % diameter stenosis ≥75%. Furthermore, 58.3% of HeFH patients with IAS exhibited concomitance of CAD, PAD or carotid stenosis. They were more likely to be older (Table). While there was no significant difference in LDL-C level, an elevated triglyceride level was observed in those with IAS (Table). Of note, during the observational period (median=14.1 years), IAS was associated with a greater likelihood of experiencing not only stroke but other cardiovascular events (all-cause death + ACS + PAD) (picture). Multivariate analysis demonstrated triglyceride level ≥1.7mmol/l as an independent predictor of IAS in HeFH patients (HR=5.53, 95% CI: 1.85–16.5, p=0.002). Conclusions Around one-fourth of HeFH patients harboured IAS, which was associated with concomitance of atherosclerosis in other vascular beds and the occurrence of stroke and other cardiovascular events. Given the relationship of IAS with hypertriglyceridemia, this lipid feature may be an important contributor to atherosclerotic formation which involves intracranial artery in HeFH patients. Clinical outcome Funding Acknowledgement Type of funding source: None

Introduction Lipoprotein (a) [Lp (a)] is a plasma lipoprotein which exhibits atherogenic properties. Lp(a) ≥50 mg/dl has been recently shown to associate with a risk of atherosclerotic cardiovascular diseases (ASCVD) in patients with heterozygous familial hypercholesterolemia (HeFH). While current guideline recommends lowering LDL-C as a first-line therapeutic approach in HeFH subjects, it remains to be fully determined whether an elevated level of Lp(a) confers additional ASCVD risks in HeFH patients who achieved a lower LDL-C level. Purpose To investigate cardiovascular outcomes in HeFH subjects with a lower LDL-C but an elevated Lp(a) levels. Methods 182 HeFH patients with on-treatment LDL-C Results The averaged LDL-C and Lp (a) levels were 1.9 mmol/l and 26.8 mg/dl, respectively. 19.2% of study subjects exhibited Lp(a)≥50 mg/dl. HeFH patients with Lp(a) ≥50 mg/dl were more likely to be older and have a history of hypertension, but these comparisons did not meet statistical significance. There was no significant difference in on-treatment LDL-C, HDL-C and Triglyceride level (Table). However, during the observational period (median=4.7 years), there was a 2.7-fold (95% CI, 1.41–5.02; p=0.004) greater likelihood of experiencing MACE in subjects with Lp(a) ≥50 mg/dl (picture). Even after adjusting clinical demographics, Lp(a) ≥50 mg/dl remained an independent predictor for the occurrence of MACE (hazard ratio=2.53, 95% CI: 1.29–4.82, p Conclusions Despite achieving on-treatment LDL-C Clinical outcome Funding Acknowledgement Type of funding source: None

The relationships between calcaneal bone mass and dietary/lifestyle habits in women at 3-4 months postpartum were examined in the context of osteoporosis prevention.Cross-sectional survey.We measured bone mass using calcaneal ultrasound in mothers who brought their 3- to 4-month-old babies to healthcare centers in Japan for health examination and administered a self-report questionnaire on physical characteristics and dietary/lifestyle habits to those who agreed to participate in the survey. Valid data were available for 1220 women (valid response rate, 97.5%).Based on their stiffness score, a measure of bone mass, 70.9% (n = 865) of the participants were classified as 'no apparent abnormality (stiffness score ≥78.8)' (low-risk group), 18.2% (n = 222) as 'guidance required (≥70.1-78.8)' (intermediate-risk group), and 10.9% (n = 133) as 'complete examination required (70.1)' (high-risk group), according to the criteria for osteoporosis screening test results. The percentage of individuals with a history of fracture was higher in the guidance required/complete examination required than in the no apparent abnormality group (P = 0.016). The analysis of relationships between the consumption frequency of certain foods, such as calcium-rich foodstuffs, and bone mass found that women who reported lower frequencies of milk and dark-colored (beta-carotene rich) vegetables for breakfast consumption had a significantly lower bone mass than those who consumed these foods more often. Furthermore, the guidance required/complete examination required group had a significantly lower calcium intake than the no apparent abnormality group (P = 0.022).These results indicate the need to provide postpartum women with dietary education programs to promote healthy eating habits, such as increased consumption of calcium-rich foods, and prevent osteoporosis.

Introduction The International Atherosclerosis Society (IAS) has proposed “severe familial hypercholesterolemia (FH)” as a FH phenotype with the highest cardiovascular risk. Coronary artery disease (CAD) represents a major atherosclerotic change in FH patients. Given their higher LDL-C level and atherogenic clinical features, more extensive formation of atherosclerosis cardiovascular disease including not only CAD but stroke/peripheral artery disease (PAD) may more frequently occur in severe FH. Methods 481 clinically-diagnosed heterozygous FH subjects were analyzed. Severe FH was defined as untreated LDL-C>10.3 mmol/l, LDL-C>8.0 mmol/l+ 1 high-risk feature, LDL-C>4.9 mmol/l + 2 high-risk features or presence of clinical ASCVD according to IAS proposed statement. Cardiac (cardiac death and ACS) and non-cardiac (stroke and peripheral artery disease) events were compared in severe and non-severe FH subjects. Results Severe FH was identified in 50.1% of study subjects. They exhibit increased levels of LDL-C and Lipoprotein (a) with a higher frequency of LDLR mutation. Furthermore, a proportion of %LDL-C reduction>50% was greater in severe FH under more lipid-lowering therapy (Table). However, during the observational period (median=6.3 years), severe FH was associated with a 5.9-fold (95% CI, 2.05–25.2; p=0.004) and 5.8-fold (95% CI, 2.02–24.7; p=0.004) greater likelihood of experiencing cardiac-death/ACS and stroke/PAD, respectively (picture). Multivariate analysis demonstrated severe FH as an independent predictor of both cardiac-death/ACS (hazard ratio=3.39, 95% CI=1.12–14.7, p=0.02) and stroke/PAD (hazard ratio=3.38, 95% CI=1.16–14.3, p=0.02) events. Clinical characteristics of severe FH Non-severe FH Severe FH P-value Baseline LDL-C (mmol/l) 5.3±1.5 6.6±2.0 50% 21.3% 49.8% Clinical outcome Conclusions Severe FH subjects exhibit substantial atherosclerotic risks for coronary, carotid and peripheral arteries despite lipid lowering therapy. Our finding underscore the screening of systemic arteries and the adoption of further stringent lipid management in severe FH patients.

Background Chronic total occlusions are still considered one of the most challenging procedures in the field of interventional cardiology and the most feared complication are the perforations. In past studies and series from Asia, Europe and United States the rate of perforations in percutaneous coronary interventions are described as 0.2% whereas this rate increases to 3% when recanalization of a chronic total occlusion is attempted. Purpose Our study sought to identify the frequency, predictors and clinical implications of coronary perforations in chronic total occlusion percutaneous interventions in a contemporary registry with data from Latin America. Methods We reported the data of a prospective multi center Latin American registry from January to December 2018 in 1066 patients who underwent chronic total occlusion percutaneous interventions in 30 centers in the following countries: Brazil, Argentina, Puerto Rico, Chile, Colombia, Ecuador and Mexico. Coronary perforation was defined as evidence of extravasation dye or blood from the coronary artery during or following the procedure. A stepwise logistic regression was performed to investigate the independent predictors of coronary perforations. Results The mean age was 64.2±10.7 years, 79.8% were male, 35.3% diabetics and 6.7% had heart failure. The most commonly involved CTO vessel was right coronary artery (41.4%), the mean J-CTO score was 2.0±1.3 and the mean CL score was 2.7±1.6. The overall procedural success rate was 81.9%. Coronary perforation occurred in 3.3% of cases: type 1 in 1.8%, Type 2 in 0.9% and Type 3 in 0.6%. In comparison with patients without coronary perforation was observed, those with such complication required more often blood transfusion (8.6% vs. 0.7%; p470 seconds (OR 6.5; 95% CI 2.4 - 17.3; p Conclusions Coronary perforation during percutaneous interventions in Latin America occurred in 3.3% of patients, being related with adverse events but not in-hospital all-cause mortality. Pharmacological management, high anatomical complexity and heart failure were identified as independent predictors of this still and so feared complication. Acknowledgement/Funding None

Background The cardiovascular event rate in Japan is much lower than that in Western countries. However, the incidence of atherosclerotic CV disease and its burden are expected to increase in the Japanese society with rapid aging, westernization of lifestyles and metabolic derangement. An increase in patients with CAD has been remarkable in spite of various preventive measures. The positive linear correlation of LDL-C level with CAD incidence along with LDL-C lowering and CAD event reduction is established by large-scale studies in Western countries, but data in Japan are limited. EXPLORE-J, observational study, was conducted to gain insights into the relationship between LDL-C management and CV events in the Japanese ACS patients. Purpose The primary objective was to evaluate the status of post-ACS lipid management and CV events in Japan. Method ACS patients aged ≥20 years were enrolled and followed up for 2 years. The primary endpoint was the incidence proportion of major adverse cardiovascular events (MACE), including CV death (death associated with MI/stroke and other CV deaths), non-fatal ACS/stroke requiring hospitalization during the observation period. Other endpoints were medications and metabolic parameters. Additional stratified analyses of MACE incidence proportions by median LDL-C reduction category (above/below absolute or % reduction) from the first measurement after ACS to V1 (Day 1 + 14 days) was also conducted. Result Of the 2016 registered patients, 1944 were analyzed. The mean age and BMI were 66.0 years and 24.2 kg/m2, respectively. At 2-year follow up, the cumulative incidence proportion of MACE was 6.8%. The cumulative incidence proportions of CV death, non-fatal ACS and stroke were 0.7%, 4.5% and 1.7%, respectively. Statin, intensive statin, and ezetimibe were prescribed, respectively, to 93.6%, 8.2%, and 3.9% at V1, and 92.3%, 10.5%, and 11.6% at V5 (Day 730±30 days). The mean LDL-C levels were 121.2, 99.4, 80.9, and 79.8 mg/dL at the first measurement after ACS, V1, V2 (Day 30±7 days) and V5, respectively. The proportions of patients who achieved LDL-C Kaplan-Meier estimates of MACE incidence Conclusion The results show the status of medical management and CV event rates in post-ACS Japanese patients. It also shows that half of the ACS patients did not achieve the recommended LDL-C levels of Acknowledgement/Funding This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.

Summary There has been no consensus on the role of serum androgen concentrations in prostate cancer detection in men with prostate-specific antigen levels of 3–10 ng/mL. In this study, testosterone and dihydrotestosterone concentrations in blood were examined by a newly developed method using ultrasensitive liquid chromatography with two serially linked mass spectrometers (LC-MS/MS). We investigated the correlation between serum androgen levels and Gleason scores at biopsy. We analyzed data of 157 men with a total prostate-specific antigen range of 3–10 ng/mL who underwent initial systematic prostate needle biopsy for suspected prostate cancer between April 2000 and July 2003. Peripheral blood testosterone and dihydrotestosterone concentrations were determined by LC-MS/MS. Blood levels of testosterone and dihydrotestosterone were compared with pathological findings by multivariate analyses. Median values of prostate-specific antigen and prostate volume measured by ultrasound were 5.7 ng/mL and 31.4 cm3, respectively. Benign prostatic hyperplasia was diagnosed in 97 patients (61.8%), and prostate cancer was diagnosed in 60 (38.2%) patients, including 31 (19.7%) patients with a Gleason score of 6 and 29 (18.5%) patients with a Gleason score of 7–10. Median values of testosterone and dihydrotestosterone in blood were 3798.7 and 371.7 pg/mL, respectively. There was a strong correlation between serum testosterone and dihydrotestosterone. In multivariate analysis, age, prostate volume, and serum dihydrotestosterone were significant predictors of benign prostatic hyperplasia or prostate cancer with a Gleason score of 6. The area under the receiver operating characteristics curve for age, prostate volume, and serum dihydrotestosterone were 0.67, 0.67, and 0.67, respectively . We confirmed that high dihydrotestosterone blood levels can predict benign prostatic hyperplasia or prostate cancer with a Gleason score of 6 in men with prostate-specific antigen levels of 3–10 ng/mL.

This study by Stockstill et al. demonstrates that bortezomib-induced neuropathic pain is driven by S1P receptor 1 (S1PR1) activation in spinal cord astrocytes. Disrupting spinal astrocyte S1PR1 signaling attenuates neuropathic pain by reducing neuroinflammation and presynaptic glutamate release., The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-specific alterations of S1pr1 did not develop neuropathic pain and lost their ability to respond to S1PR1 inhibition, strongly implicating astrocytes as a primary cellular substrate for S1PR1 activity. At the molecular level, S1PR1 engaged astrocyte-driven neuroinflammation and altered glutamatergic homeostasis, processes blocked by S1PR1 antagonism. Our findings establish S1PR1 as a target for therapeutic intervention and provide insight into cellular and molecular pathways. As FTY720 also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.

Giant cell arteritis (GCA)-type arteritis, granulomatous arteritis with multinucleated giant cells and destruction of the inner elastic layer, occurs in several arteries (1, 2). However, diagnosis ...

Purpose Magnitude of functional recovery of the left ventricle (LV) is one of the critical determinants of prognosis post-implantation of ventricular assist device (iVAD) for non-ischemic dilated cardiomyopathy (NIDCM). Although predictive factors of the functional recovery are not fully understood, presence of immunocompetent cells in the myocardium is reported to be associated with the pathological stage and/or the myocardial viability. We aimed to explore relationships between functional recovery post-iVAD implantation and distribution of the immunocompetent cells in NIDCM. Methods In the last 5 years, iVAD such as HeartMateII was implanted in 50 patients with NIDCM for bridge-to-transplantation purpose, followed by β blocker and/or ACE inhibitor in the aim to enhance functional recovery. Results During the iVAD support, 12 patients (24%) underwent heart transplantation, while 2 patients (4%) died due to cerebral infarction. Four patients (8%) were treated for congestive heart failure in-hospital, while freedom from heart failure was 96±0.0% at 1 year and 89±0.1% at 5 years. Echocardiographical dimension of the LV was a significant predictive factor of heart failure post-iVAD implantation (P Conclusion Despite aggressive medical treatments post-iVAD implantation, functional recovery was not frequently seen in advanced stage of NIDCM. Immunocompetent cells in the LV myocardium might be a key to predict myocardial viability of this pathology.

Severe adverse events (SAE) and late hematological malignancies have been reported after PBSC donation. No prospective data on incidence and risk factors have been available for family donors so far. The Japan Society for Hematopoietic Cell Transplantation (JSHCT) introduced therefore in 2000 a mandatory registration system. It defined standards for donor eligibility and asked harvest centers to report any SAE immediately. All donors were examined at day 30 and were to be contacted once each year for a period of 5 years. Acute SAEs within day 30 were reported from 47/3264 donations (1.44%) with 14 events considered as unexpected and severe (0.58%). No donor died within 30 days. Late SAEs were reported from 39/1708 donors (2.3%). The incidence of acute SAEs was significantly higher among donors not matching the JSHCT standards (P=0.0023). Late hematological malignancies in PBSC donors were not different compared with a retrospective cohort of BM donors (N:1/1708 vs N:2/5921; P=0.53). In conclusion, acute and late SAEs do occur in PBSC donors at relatively low frequency but risk factors can be defined.

Background To clarify the influence of hypertension and blood pressure ( BP ) control on thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐ RHYTHM Registry was performed. Methods and Results A consecutive series of outpatients with atrial fibrillation was enrolled from 158 institutions. Of 7937 patients, 7406 with nonvalvular atrial fibrillation (70.8% men, 69.8±10.0 years) were followed for 2 years or until an event occurred. Hypertension was defined as a systolic BP ≥140 mm Hg, a diastolic BP ≥90 mm Hg, a history of hypertension, and/or antihypertensive drug use. Hypertension was an independent risk factor for major hemorrhage (hazard ratio 1.52, 95% CI 1.05–2.21, P =0.027) but not for thromboembolism (hazard ratio 1.05, 95% CI 0.73–1.52, P =0.787). When patients were divided into quartiles according to their systolic BP at the time closest to the event or at the end of follow‐up (Q1, CI 1.75–4.74, P CI 1.02–2.53, P =0.041) after adjustment for components of CHA 2 DS 2 ‐ VAS c score, warfarin use, and antiplatelet use. A systolic BP of ≥136 mm Hg was an independent risk factor for thromboembolism and major hemorrhage. Conclusions BP control appears to be more important than a history of hypertension and baseline BP values at preventing thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation. Clinical Trial Registration URL : http://www.umin.ac.jp/ctr . Unique identifier: UMIN 000001569.

On April 11, 2014, the Government of Japan made the decision to approve the Strategic Energy Plan. Then, on June 23, 2014, the Council for a Strategy for Hydrogen and Fuel Cells established by the Ministry of Economy, Trade and Industry compiled a Strategic Road Map for Hydrogen and Fuel Cells, containing all the measures to be taken by those involved in realizing a hydrogen society. In December 2015, fuel cell vehicles will begin to be sold commercially and hydrogen refueling stations are supposed to be constructed in about 100 places, mainly in the four major metropolitan areas in Japan.

Objectives To examine the association between atypical antipsychotic medications and incident treatment for diabetes mellitus or hyperlipidemia in elderly adults without diagnoses of schizophrenia or bipolar disorder. Design Two case–control studies using medical and pharmacy claims data. Setting United States managed care population from multiple insurance plans. Participants Individuals aged 65 and older enrolled in a Medicare Advantage or commercial (health maintenance organization) managed care health plan in the western United States with no claims indicating diagnosis of schizophrenia or bipolar disorder in the 1 year pre-index period. Cases were defined as persons newly initiated on an antidiabetic (n = 13,075) or antihyperlipidemic (n = 63,829) medication on the index date. For the new diabetes mellitus analysis, 65,375 controls were matched to cases based on age, sex, health-plan type, and index date year. In the new hyperlipidemia analysis, 63,829 controls were matched to cases based on the same variables. Measurements Conditional logistic regressions were performed to determine the odds of initiated antidiabetic or antihyperlipidemic medication for participants exposed to atypical antipsychotics compared with those with no exposure. The models included comorbidities possibly associated with the outcome. Results Exposure to atypical antipsychotics was associated with significantly greater adjusted odds of starting an antidiabetic medication (1.32, 95% confidence interval (CI) = 1.10–1.59) but significantly lower odds of starting an antihyperlipidemic medication (0.76, 95% CI = 0.67–0.87). Conclusion Use of atypical antipsychotics in older adults for conditions other than schizophrenia and bipolar disorder was associated with incident treatment of diabetes mellitus but not of hyperlipidemia, suggesting that older adults may be susceptible to the adverse metabolic consequences of these agents.

Introduction: The effect of in vitro fertilization (IVF) on neurodevelopmental outcome is unclear. Probably, IVF does not affect traditional measures of neurological development in infancy, but little is known on long-term effects. Recently a new video-based instrument to evaluate neuromotor development was developed. The Infant Motor Profile (IMP) evaluates neuromotor condition in infants in terms of the quality of spontaneous motor behaviour. The IMP does not only assess traditional neuromotor domains, such as performance, symmetry and movement fluency, but also two novel domains: variation and variability. Movement variation denotes the size of the child's movement repertoire. Previous studies demonstrated that reduced movement variation is associated with early lesions of the periventricular white matter and - more generally - reflects the integrety of cortical connectivity. In addition, reduced variation during infancy is associated with neurodevelopmental disorders in later life and reduced intelligence at school age. Variability denotes the child's ability to select from the repertoire of movements the strategy that suits the situation best. In this prospective, assessor-blinded cohort study, we address the question whether ovarian hyperstimulation and/or the in vitro procedure affect movement variation during infancy. Material and Methods: Singletons born following IVF with conventional controlled ovarian hyperstimulation (COH-IVF, n = 68), following IVF in a modified natural cycle (MNC-IVF, n = 57) and following natural conception born to subfertile couples (Sub-NC, n = 90) were assessed with the IMP at 4, 10 and 18 months. The assessment resulted in a total IMP score and 5 domain scores: variation (i.e. the size of movement repertoire), variability (i.e. the ability to select motor strategies), symmetry, fluency and performance. Primary outcome was the domain score variation. Outcome variables were analyzed with a mixed effects model. Results: The mixed model indicated an overall effect of treatment on variation (p Conclusions: The preliminary data suggest that ovarian hyperstimulation may be associated with reduced movement variation in infancy. These findings stress the need to carefully monitor neurodevelopment in IVF offspring.

SUMMARY Purpose: To determine if switching from select branded to generic equivalent antiepileptic drugs (AEDs) in patients with epilepsy is associated with adverse outcomes. Methods: A retrospective cohort study using a large health insurance plan claims database comparing patients with epilepsy who switched from brand to generic equivalent phenytoin, lamotrigine, or divalproex after 6 months (switch cohorts) to matched patients who remained on the brand (nonswitch cohorts). Primary outcomes measured include the incidence rate ratio (IRR) of discontinuation of the index AED; change in dose of index AED or addition of another AED; and the event rate ratio (ERR) of the composite of all-cause emergency department (ED) visits or hospitalizations. Key Findings: Lamotrigine and divalproex showed no differences in AED utilization changes between the switchers and nonswitchers [IRR for lamotrigine 1.00, 95% confidence interval (CI) 0.84‐1.19; IRR for divalproex 1.02, 95% CI, 0.88‐1.42]. Compared with nonswitchers, the phenytoin switch cohort had greater incidence of AED utilization changes (IRR 1.85, 95% CI 1.50‐2.29). The switch versus nonswitch cohorts did not demonstrate differences in ED visits or hospitalizations for the studied AEDs (ERR for phenytoin 0.96, 95% CI 0.80‐1.16; ERR for lamotrigine 0.97, 95% CI 0.80-1.17; ERR for divalproex 0.83, 95% CI 0.66‐1.06). Significance: Brand to generic switching of phenytoin was not associated with more clinical events but was associated with increased index drug discontinuations, dose changes, or therapy augmentations. Lamotrigine or divalproex brand to generic switching was not associated with increased incidence of events or utilization changes compared with patients remaining on the branded product. Changes in AED utilization may be more sensitive than ED visits and hospitalizations for detecting adverse outcomes.

To examine medication adherence among Medicare Part D beneficiaries initiating oral anti-diabetic medications and explore whether there is any association of using mail-order pharmacy (vs. retail pharmacy) with better adherence in this patient population.Using administrative pharmacy claims data, we conducted a retrospective cohort study on Medicare Part D beneficiaries who newly initiated oral anti-diabetic treatment between July 1, 2008 and December 31, 2008. Mail-order pharmacy users were matched to retail pharmacy users via propensity scoring, controlling for patient demographic and clinical characteristics. Adherence with oral anti-diabetic medications during the benefit year of 2009 was assessed using the proportion of days covered (PDC). Comparison of medication adherence between the mail-order pharmacy group and retail pharmacy group was conducted in the propensity matched sample using the paired t-tests and McNemar's tests.A total of 22,546 patients who initiated oral anti-diabetic medications were identified. The average PDC was 0.60 and only 41.6% of the study population attained good adherence (defined as PDC ≥ 0.8) with oral anti-diabetic medications during calendar year 2009. The matched sample included 1361 patients in each of the mail-order and retail pharmacy cohorts. Compared with the retail pharmacy group, mail-order pharmacy users demonstrated a significantly higher PDC (0.68 vs. 0.61; P 0.001) throughout the benefit year. More patients in the mail-order pharmacy group (49.7%) attained good adherence with their oral anti-diabetic medications compared to 42.8% in the retail pharmacy group (P 0.001).The study was subject to limitations inherent in retrospective claims database analysis.Adherence with oral anti-diabetic medications among Medicare Part D beneficiaries is suboptimal. Patients using mail-order pharmacy had better adherence to oral anti-diabetic medications than those who used retail pharmacies. However, the causal relationship between mail-order pharmacy use and adherence should be further examined in a randomized study setting.

BACKGROUND: A national pharmacy benefits management company implemented a rheumatoid arthritis (RA) disease therapy management (DTM) program as an enhanced offering to patients receiving specialty pharmacy services. The program was designed to improve medication adherence, maximize therapeutic outcomes, and enhance physical functioning and health-related quality of life (HRQOL) by empowering patients and improving their knowledge of RA. OBJECTIVES: To evaluate (a) adherence to injectable RA medications for patients participating in an RA DTM program compared with nonparticipating patients receiving injectable RA medications at specialty or community pharmacies and (b) HRQOL, work productivity, and physical functioning before versus after completing the RA DTM program. METHODS: Patients who had an RA diagnosis and a pharmacy claim for an injectable RA medication during the identification period (August 2007 through September 2008) and were continuously enrolled with the plan from 4 months before through 8 months after the identification date were stratified into 3 patient cohorts: DTM, specialty pharmacy, and community pharmacy. DTM patients were further categorized into a DTM intent-to-treat (ITT) cohort (all 340 DTM-enrolled patients) and a DTM completer cohort (subset of 266 ITT patients who completed the month 6 consultation). DTM completer, specialty, and community pharmacy cohorts were matched 1:1:1 (n = 244 in each cohort after matching) using a propensity score that represented the likelihood of completing the DTM program. The primary outcome was adherence to injectable RA medications, measured as the proportion of days covered (PDC) over an 8-month post-identification period. Patient-reported outcomes (short form [SF]-12, Work Productivity Activity Impairment [WPAI], and Health Assessment Questionnaire-Disability Index [HAQ-DI]) were evaluated among all 371 DTM patients who completed the month 0 and month 6 consultations regardless of whether they met continuous enrollment requirements (patient-reported sample). RESULTS: Of specialty pharmacy patients, approximately 14% chose DTM participation. During the post-identification period, mean PDC was 0.83 for DTM ITT, 0.89 for DTM completer, 0.81 for specialty pharmacy, and 0.60 for community pharmacy patients. Differences were statistically significant for both DTM cohorts compared with the community pharmacy cohort (P < 0.001) and for the DTM completer cohort compared with the specialty pharmacy cohort (P < 0.001), but not for the DTM ITT cohort compared with the specialty pharmacy cohort (P = 0.291). In the patient-reported sample, mean SF-12 physical component scores significantly increased by 1.1 points (P = 0.048); mean SF-12 mental component scores were not significantly changed (P = 0.679); mean WPAI work productivity decreased by 10.8 percentage points (P = 0.045); and mean HAQ-DI scores significantly improved by 0.08 points (P < 0.001). CONCLUSIONS: Patients participating in the RA DTM program had significantly higher injectable RA medication adherence compared with community pharmacy patients. Adherence to injectable RA medications was significantly higher for patients completing the RA DTM program, but not for the DTM ITT group, compared with patients receiving specialty pharmacy services alone. Patients completing the RA DTM program experienced improvements in SF-12 physical component and HAQ-DI scores but did not demonstrate improvements to SF-12 mental scores or work productivity.

Background The eating habits of mothers and children in infancy are important. It is not only impact their own present health, but may effect children's health of lifelong, since early childhood is a crucial moment to formulate basic lifestyle habits. The mothers raise children in infancy could implement healthy lifestyle to prevent lifestyle related diseases of children in future. The aim of this study is to describe eating habits of mothers and their children in Japan. Method A self-administered questionnaire was distributed to women who have children whose age were 3 to 6-years-old at three nursing schools in a regional town, Japan. The questionnaire was about their demographics, lifestyle, and eating habits of mothers and their children. Results In total, 113 women were answered. We excluded the women's data with missing variables. As a result of the exclusion, 95 mothers and their children were the analysis subjects for this research. There were no mothers and children who were on a dietetic treatment. The mean age of women was 36.4 ± 5.3-years-old. The mean age of their children was 4.5 ± 1.0-years-old. The mean body mass index (BMI) of mothers was 21.8 ± 3.4. The mean Kaup index of children was 15.5 ± 1.8. There were 13 (13.7%) women who were underweight (BMI is below 18.5), 68 (71.6%) women were normal weight status (BMI is 18.5 to 24.9), and 14 (14.7%) women who were in overweight status (BMI is more than 25.0). There were 34 (35.8%) children who were underweight (Kaup index is below 15.0), and 68 children who were in normal weight status (Kaup index is 15.0 to 17.9). The number of children who were in overweight status (Kaup index is more than 18.0) was 14 (14.7%). In this study, many mothers and their children had good eating habits. For example, most of the mothers (80.0%) and their children (91.6%) were eating breakfast every day. There was no association between mothers’ and children's good eating habits. While, there were 73 (76.8%) children and 70 (73.7%) mothers who do something at meals, as an example, they were in the habit of watching television while eating. The agreement of this habitual practice between mothers and children was substantial by kappa statistics (κ = 0.633). In regards to dietary supplements use, four children (4.2%) were using dietary supplements including calcium, minerals, or multivitamins, and one child used it before. On the other hand, 47 (49.7%) mothers used to have dietary supplement, and 11 (11.7%) mothers were using some supplements. Discussion The rate of dietary supplements use among Japanese children is lower than children in the United States, Australia and China. We, however, suppose that Japanese children using dietary supplements increase thought the effectiveness is not clear yet. A previous study showed that Japanese mothers who were supplement user tended to use dietary supplements for their children. The number of women who have experience of dietary use is increasing in Japan. There, therefore, is possibility of using supplement for children will increase in Japan. Health education including dietary supplements use is a pressing public health issue to develop healthy dietary habits for mothers and children.

We evaluated profiles of B, P, As, and Si implanted in Ge substrates by secondary ion mass spectrometry, analyzed the profile data using a quasi-crystal Lindhard-Scharff-Schiott (QCLSS) theory, tuned its parameters, and established a corresponding database based on a tail function. We also predicted Ge, Sb, Ga, In, and Xe profiles in Ge substrates by using the QCLSS theory and also established a corresponding database. We further evaluated the thickness of the amorphous layers formed by ion implantation by transmission electron microscopy and reproduced it in a model by tuning a corresponding parameter of the through dose. Using a profile parameter database and this through dose, we can predict ion implantation profiles and related amorphous layer thicknesses in Ge substrates over a wide range of ion implantation conditions.

The purpose of this study was to examine the sport experience for athletes with intellectual disabilities (ID) who participate in Special Olympics (SO). This study included a nationally representative sample of 1,307 families and 579 athletes in the U.S., focusing on sport involvement over the lifespan and motives for participating and for leaving SO. Athletes with ID are similar to athletes without disabilities in that sport is a significant life experience. They participate in sport for fun (54%) and social interaction (21%). Like athletes without disabilities, SO athletes leave sport because of changes in interest (38%) but also because of program availability (33%). These findings suggest that we continue to document the involvement of people with ID in sports and work to expand the sport opportunities available.

Purpose Controversy surrounds the question whether thiazolidinediones (TZDs) increase the risk of acute myocardial infarction (AMI). This study examined risk of AMI in patients with type 2 diabetes mellitus (T2DM) who were taking TZDs or other antidiabetic medications. Methods Using a nested case-control design, a cohort of patients aged 18–84 years with T2DM and use of an oral antidiabetic medication or exenatide between January 2002 and June 2006 was identified. Cases of AMI were matched with up to four controls based on age, gender, health plan, geography, and diabetes therapy regimen. Over the 1-year pre-index period, TZD exposure was compared with no TZD exposure, after adjustment for potential confounders. Results Overall, 1681 cases were identified and matched with 6653 controls. Compared with no TZD exposure, an increased risk of AMI was not observed among TZD exposed patients (adjusted OR 1.01; 95%CI, 0.85–1.20; adjusted p = 0.98). When exposure proximity to the event was examined, the risk of AMI was significantly increased with recent rosiglitazone exposure between 1 and 60 days prior to the case date (adjusted OR 1.69; 95%CI, 1.18–2.44; adjusted p = 0.045) and was not significantly increased with current or remote rosiglitazone exposure or current, recent, or remote pioglitazone exposure. Conclusion TZD exposure did not increase the risk of AMI when exposure proximity was not considered. However, when evaluating exposure proximity to the event, the risk of AMI was increased with recent rosiglitazone exposure between 1 and 60 days prior to the case date. Copyright © 2008 John Wiley & Sons, Ltd.

BACKGROUND: The cardiovascular (CV) benefits of lipid-lowering therapy in older adults with hypercholesterolemia and underlying risk factors for coronary artery disease (CAD) have been well documented. Significant reductions in the risk of myocardial infarction (MI) and coronary death have been demonstrated with statin therapy, benefits that are of particular relevance in patients with diabetes. Managed care interventions with prescribers have increased the use of selected drugs such as statins. OBJECTIVES: To (1) measure the increase in new users of statins associated with the implementation of a statin initiation intervention aimed at prescribers for Medicare Part D Medication Therapy Management Program (MTMP) members with diabetes or CAD and (2) estimate the potential cost savings associated with the projected reduction in CV events based on published controlled trials. METHODS: Medicare Advantage Prescription Drug (MA-PD) and

The effect of mechanical stress on Barkhausen noise from 45-permalloy plate is reported for as-rolled plate and plates which are annealed at various temperatures up to 1000 K. The data are compared with data of magnetic permeability, coercive force and Vickers hardness. The Barkhausen noise energy detected has been found to increase linearly with nominal stress. The larger the annealing temperature, the less the rate of increase was observed. On the other hand, the magnetic permeability has been found to decrease linearly with nominal stress in a small stress region. Overall features are explained qualitatively by a model in which tensile stress makes the number of effective pinning sites which have appropriate activation energies for discontinuous motion of domain wall more, while annealing process makes just the number of pinning sites such as defects and grain boundaries less.

BACKGROUND: Transforming growth factor (TGF)-beta plays an important role in the regulation of airway inflammation and remodelling in asthma. Recent studies suggest that TGF-beta(2) is a predominant isoform expressed in severe asthma and it is also associated with airway remodelling. OBJECTIVE: To determine whether the polymorphisms in TGF-beta(2) are associated with childhood atopic bronchial asthma in a Japanese population. METHODS: We identified a total of eight polymorphisms and characterized the linkage disequilibrium (LD) mapping of the gene. Three variants in the promoter and 3'UTR were genotyped, and we conducted an association study of TGF-beta(2) (childhood atopic asthma n=297, normal controls n=555). An association analysis of these variants and an expression and functional analysis were performed. RESULTS: 3'UTR 94862T >A was found to be significantly associated with the risk of childhood atopic asthma (P=0.00041). The -109-->ACAA ins promoter variant was also associated with the risk of childhood atopic asthma (P=0.0037). TGF-beta(2) expression was observed in both the normal and asthmatic bronchial epithelium, and both real-time PCR and an ELISA showed a significant basal and TGF-beta(1)-induced TGF-beta(2) expression in the bronchial epithelial cell line BEAS2B. Furthermore, the promoter variant -109-->ACAA ins increased the TGF-beta(2) promoter-reporter activity in BEAS2B cells. CONCLUSIONS: Our data suggest that TGF-beta(2) may therefore be involved in the development of childhood atopic asthma by means of functional genetic polymorphism. The polymorphisms in TGF-beta(2) may become important information for asthma susceptibility in children.

In this paper, we propose a method for calculating probability of scores for men's team competition in artistic gymnastics. We here assume each gymnast's score as a normal distribution and provide a mathematical formulation for 6-5-4 format in the team competition. By setting the different mean and standard deviation (SD) of the normal distribution, we calculate the distributions of the team score, and obtain the relationship between the mean and SD of each gymnast and the expected number of the team score. We demonstrate an application of this method in the selection of five gymnasts to compete in each event.

Retrospective analysis has shown that activating mutations in exons 18-21 of the epidermal growth factor receptor (EGFR) gene are a predictor of response to gefitinib. We conducted a phase II trial to evaluate the efficacy and safety of gefitinib as first-line therapy for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Patients with stage IIIB or IV chemotherapy-naïve NSCLC with EGFR mutation were treated with 250 mg gefitinib daily. For mutational analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations (deletions in or near E746-A750, n=16; L858R, n=4). Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75% (95% CI, 48-93%). After a median follow-up of 12.7 months (range, 3.1-16.8 months), 10 patients demonstrated disease progression, with median progression-free survival of 8.9 months (95% CI, 6.7-11.1 months). The median overall survival time has not yet been reached. Most of the toxicities were mild. This study showed that gefitinib is very active and well tolerated as first-line therapy for advanced NSCLC with EGFR mutations.

This paper discusses jumping pattern generation for a serial link robot in order to maximize its jump height under torque limitation. By applying a genetic algorithm (GA) for determining torque assignment, we obtain various jumping patterns with respect to the torque limitation for a fixed mass of the robot. With the increase of the torque limitation, double-leg based jump, single-leg based jump, and spring-type jump are generated for achieving the largest jump height. Under an additional joint angle limitation, we also obtain an interesting solution where one end of the link is first lifted up and the other end finally kicks the ground strongly

症例1: 75歳,女性.腹痛にて近医で加療中であったが,イレウス症状が強くなったため当科に紹介された. CTにて門脈ガス(PVG)血症・著明な腸管ガス像,血液検査にてCRP 36.81mg/dl・CPK 1,4571U/Lと上昇しており急性腸間膜動脈閉塞を疑い緊急手術を行った.回腸末端130cmおよび上行結腸10cmまで腸管壊死を認め切除・小腸痩を造設した.術後ICU管理を必要としたが125日目に軽快・転院となった. 症例2: 66歳,男性.嘔吐・腹痛を主訴に当科紹介となる. CTにてPVGを認めるもCRP 5.23mg/dl,筋性防御・反跳痛は認められず保存的治療を施行した.入院後,大量の便とともに症状は消失し20日目に退院した. 症例3: 66歳,男性.急激な腹痛・嘔吐にて当院受診した. CTにて門脈ガス血症を認めるもCRP5.34mg/dl,筋性防御・反跳痛は認められず保存的治療を施行した. DMのためα-グルコシダーゼ阻害剤内服中でありこれに起因する腸管内圧上昇によるPVGと考えられた.

Objective To evaluate the indications for transvaginal saline contrast sonohysterography (TV-SCSH) in endometrial screening by transvaginal sonography in infertile women. Methods The study involved 850 consecutive infertile women presenting to an outpatient clinic. Using transvaginal ultrasound endometrial images were evaluated in the proliferative phase. Abnormal images were classified as follows: rugged (R), hyperechoic (H), waved (W), or thick (T). Clinical symptoms such as hypermenorrhea, dysmenorrhea and abnormal uterine bleeding were also recorded. Abnormal endometrial images were further evaluated on TV-SCSH. Age-matched women with normal endometrial images underwent TV-SCSH as controls. Results The endometrial pattern was abnormal in 111 patients (13.1%). Lesions that had been identified by TV-SCSH including endometrial polyps (44 cases), submucosal myomata (29 cases), and intramural myomata with mucosal extension (24 cases) were largely associated with the R and/or the H pattern, the W or the T pattern, and the W pattern, respectively. Sensitivity and specificity of the abnormal endometrial image for any lesion were 100% and 91.5%, respectively. Sixty-four patients (59.3%) were asymptomatic despite an abnormal endometrial image. Conclusions TV-SCSH should be performed on selected patients following assessment of endometrial images on transvaginal sonography in order to diagnose intra- and pericavitary lesions in infertile women. Copyright © 2004 ISUOG. Published by John Wiley & Sons, Ltd.